Cutaneous squamous cell carcinoma

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.

See “Head and neck carcinomas” and “Anogenital manifestations of HPV infection” for diagnosis and management of squamous cell carcinoma of the head, neck, and genitals.

• Incidence ^[1][2]
  • Second most common form of keratinocyte carcinoma after basal cell carcinoma ^[3][4]
  • ∼ 20% lifetime risk for non-Hispanic white individuals; incidence is rising ^[1]
  • Incidence increases with age and proximity to the equator ^[5]
• Sex: ♂ > ♀ (3:1) ^[1][3]
• Annual disease-specific mortality: 1.5–2% ^[1]

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: ^[1][2][3]
  • Light skin tones
  • History of sunburns or recreational tanning
  • Close geographic proximity to the equator
• Male sex ^[1][3]
• Older age; SCC typically affects individuals > 60 years of age. ^[1][3]
• Chronic immunosuppression (e.g., HIV, solid organ transplant recipient) ^[4]
• Exposure to chemical carcinogens (e.g., coal tars, arsenic) or ionizing radiation ^[1][2][3]
• Chronic inflammation, e.g.: chronic wounds (see “Marjolin ulcer”) ^[2][6]
• High-risk human papillomavirus infection (for anogenital and periungual SCC) ^[1][3]
• Genetic predisposition ^[1][2][4]
  • Xeroderma pigmentosum
  • Albinism

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. ^[2]

Invasive cSCC ^[2]

• Characteristic features include:
  • Nonhealing hyperkeratotic papule or plaque
  • Easy friability (i.e., bleeds easily after minor trauma)
  • Central ulceration
  • Hyperkeratosis
• Location ^[2]
  • Typically occurs on sun-exposed areas
    • Dorsal aspect of forearms and hands (most common)
    • Head, and neck (including ears and lip)
  • Atypical areas
    • Areas not exposed to the sun: more common in individuals with darker skin tones or chronic inflammatory skin conditions
    • Subungual and anogenital SCC: associated with high-risk HPV infection ^[1][3]

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). ^[2]

Metastatic cSCC

Metastases occur in ∼ 3% of individuals with cSCC; risk is higher in immunosuppressed individuals. ^[2][7]

• cSCC Can spread through the nervous, lymphatic, or vascular systems
• Perineural invasion can manifest as pain, numbness, and/or weakness.
• Most common sites for metastasis include lymph nodes (80%), lungs, liver, brain, and bone ^[7]

Keratoacanthoma ^[1][2][8]

Keratoacanthoma is a well-differentiated squamoproliferative keratotic lesion that is now considered a low-risk histologic variant of SCC. ^[1][2][8]

Epidemiology ^[8][9]

• Common; true incidence is unknown
• Most commonly occurs in adults > 40 years of age
• ♂ > ♀

Risk factors ^[8][9][10]

• 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 Muir-Torre syndrome ^[11][12]

Clinical features ^[8][9][10]

• 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. ^[10]

Diagnostics ^[8][9][10]

Keratoacanthoma may be clinically indistinguishable from invasive cSCC on clinical examination and dermoscopy. Biopsy is required for diagnostic confirmation.

• Biopsy: full-thickness excisional biopsy or punch biopsy ^[10]#27967]
• Histopathology: ^[1][3]
  • Central, hyperkeratotic crater surrounded by well-differentiated squamous epithelium ^[13]
  • Atypical and/or dyskeratotic keratinocytes ^[13]

Differential diagnoses ^[10][13]

• cSCC
• Wart
• Actinic keratosis

Treatment ^[8][10]

Keratoacanthoma should be treated as cSCC. ^[2]

• Early excision is preferred.
  • Wide local excision
  • Mohs micrographic surgery
• If surgery is not feasible or if multiple lesions are present: Consider systemic retinoids or intralesional injection of chemotherapeutic agents ^[10]
• Long-term monitoring after excision is recommended to identify recurrence or new skin tumors; see “Follow-up for cSCC.”

Prognosis ^[8][9]

• Spontaneous regression can occur within 12 months in some cases.
• Rarely, metastasis can occur.
• Risk of recurrence after excision: up to 8% ^[8]

Marjolin ulcer ^[6]

A Marjolin ulcer refers to the malignant transformation of preexisting chronic skin inflammation or scar tissue.

Clinical features

• Nodule with induration
• Nonhealing ulcer with rolled edges and granulation tissue
• Frequently occurs on the lower extremities in areas with, e.g:
  • Ulcers (e.g., pressure or venous ulcers)
  • Scars (e.g., burn scars)
  • Osteomyelitic fistulas

Diagnostics

• Skin biopsy (e.g., punch biopsy)
• Histology findings: typically well-differentiated squamous cell carcinoma; BCC or melanoma can also occur

Treatment

• Frequently requires wide-margin excision with skin grafting
• Alternative options, e.g.: Mohs surgery or amputation above the lesion

General principles ^[3][4][14]

• A comprehensive clinical examination in patients with suspected cSCC should include:
  • Examination of the lesion; dermoscopy can support visual inspection ^[15][16]
  • Examination of the draining lymph nodes; examination of the parotid gland as needed
  • A full-body skin examination to assess for concurrent precancerous lesions and other skin cancers
• A skin biopsy is required for diagnostic confirmation and risk stratification.
  • Biopsy all lesions suspicious for cSCC.
  • The biopsy specimen should include the deep reticular dermis. ^[1][17]
• 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 ^[3][16][18]

• Characteristic vascular features
  • Looped (hairpin) vessels and serpentine vessels
  • Glomerular vessels
  • Small dotted vessels
• Pigmented features of cSCC ^[3]
  • Gray-brown homogeneous pigmentation
  • Small brown globules
• Other features ^[18][19]
  • Keratin
  • Small white circles or white structureless areas ^[16]
  • Ulceration
  • Blood spots

Actinic keratosis has a strawberry pattern on dermoscopy: yellow or white dots or haloes on an erythematous background. ^[16]
Suspect invasive cSCC if looped and serpentine vessels are seen on dermoscopy. ^[3]

Skin biopsy ^[2][14]

Select a biopsy technique based on the clinical features of the lesion and procedural risks ; use shared-decision making.

• Techniques:
  • Shave biopsy for a raised lesion
  • Punch biopsy of the most abnormal area of a large lesion
  • Full-thickness excisional biopsy is preferred for lesions with pigmented features of cSCC to rule out melanoma. ^[2]
  • Consider complete excision (with appropriate margins) as a diagnostic and therapeutic procedure for small lesions. ^[14]
• Ensure adequate sample size and depth for histopathological examination; if not, a repeat biopsy may be required. ^[17]
• To optimize the quality of the pathology report, the following information should be included with the biopsy samples: ^[17]
  • Patient demographics
  • Presence of risk factors for cSCC
  • Size and morphology of the lesion
  • Initial sample or repeat biopsy

Perform a full-thickness excisional biopsy if there is any concern for malignant melanoma (e.g., pigmentation, ABCDE criteria). ^[2]

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. ^[20]

Precancerous cSCC (Actinic keratosis)

• Histopathology
  • Atypical keratinocytes in the basal and squamous layers
  • Hyperkeratosis and parakeratosis
  • Granular layer is usually absent.
• Progression ^[2]
  • ∼ 60% of cSCC lesions arise from AK.
  • ∼ 20% progress to invasive cSCC.
  • ∼ 50% resolve spontaneously

Carcinoma in situ (Bowen disease)

• Histopathology: atypical keratinocytes confined to the epidermis
• Progression: ∼ 3% progress to invasive cSCC ^[21]

Invasive cSCC

• Histopathology ^[20]
  • Atypical keratinocytes cross the basement membrane of the epidermis and invade the dermis. ^[7]
  • 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
• Progression
  • 3–4% become metastatic (higher in immunosuppressed individuals). ^[14]

High-risk histological subtypes of cSCC ^[3]

• Desmoplastic
• Acantholytic
• Spindle cell
• Adenosquamous
• carcinosarcomatous cSCC.

Low-risk histological subtypes of cSCC ^[3]

• Keratoacanthoma
• Verrucous carcinoma
• Buschke Loewenstein tumor

• Seborrheic keratosis
• Warts
• Precancerous skin lesions
• Keratoacanthoma
• Basal cell carcinoma
• Malignant melanoma
• Merkel cell carcinoma ^[14]

The differential diagnoses listed here are not exhaustive.

Assessment of disease extent ^[1][14]

Refer patients with high-risk features of cSCC to a specialist (e.g., oncologist) to evaluate for locoregional, nodal, and distant metastases. This may include:

• Imaging
  • CT with IV contrast: for suspected spread to soft tissue, bone, or lymph nodes
  • PET-CT or ultrasound: for lymph node metastasis ^[14]
  • MRI: for suspected perineural, brain, or eye involvement ^[1]
• Sentinel lymph node biopsy

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. ^[1][14]

Staging ^{[1][14][23][24]}

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 ^[14]

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
  • Lesions with any high-risk feature of cSCC
  • These lesions are associated with a high-risk of recurrence, metastasis, and disease-related mortality.
• Low-risk cSCC: lesions with no high-risk features of cSCC

General principles ^[2][4][14]

• Definitive treatment of cSCC is recommended.
• The choice of therapy is based on:
  • Risk of recurrence (see “cSCC risk stratification ”)
  • Need for conservation of tissue and function
  • Patient expectations (use shared decision-making)
• Treatment options include:
  • Resection : generally preferred as it is associated with the lowest recurrence rates
  • Radiotherapy (RT): when resection is not feasible
  • Chemotherapy: for locally advanced or metastatic cSCC
• Consults and referrals
  • Consider referral to a dermatologist for management.
  • Multidisciplinary care is necessary for patients with high-risk cSCC lesions, those who cannot undergo surgery, and those with metastatic disease. ^[1]
• Ensure appropriate follow-up for cSCC to assess for recurrence or development of subsequent skin cancers.

Overview of treatment options ^[4][14]

Topical pharmacotherapy and photodynamic therapy are not recommended for the treatment of cSCC. Adjuvant photodynamic therapy after resection may be considered for high-risk cSCC lesions. ^[14]

Localized cSCC ^[1][4][14]

High-risk cSCC

• Preferred: MMS
• Alternatives
  • Surgical excision with wide margins; consider delayed closure until R0 resection is confirmed.
  • RT ± systemic therapy for patients who cannot undergo resection
• Consider adjuvant RT for patients with perineural involvement.

Low-risk cSCC

• Preferred
  • Standard surgical excision (4–6 mm margins) ^[1][14]
  • MMS
  • 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
  • Cryotherapy

Locally advanced or metastatic cSCC ^[1][4][14]

Specialist referral and multidisciplinary care are recommended to consider the following options:

• Surgical resection ± lymphadenectomy
• Adjuvant RT
• Systemic therapy
• Palliative care
• Enrollment into clinical trials

Follow-up for cSCC ^[1][4][14]

• 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. ^[1]
• Treat actinic keratoses at diagnosis.
• Encourage adherence to photoprotective measures.
• Educate patients and/or caregivers on self-examination to detect recurrence, new lesions, and lymph node enlargement.

A comprehensive skin examination and lymph node examination should be performed at each follow-up visit. ^[14]

• 5-year survival rate: ≥ 90% ^[4]
• Individuals with a history of cSCC are at an increased risk of developing subsequent cSCC and other skin cancers (BCC, melanoma). ^[1][14]
• cSCC accounts for ∼ 20% of all deaths caused by skin cancers. ^[7]

Unresectable locoregional disease is the most common cause of cSCC-related mortality. ^[24]

• Screening: Consider recommending regular skin self-examination (e.g., monthly). ^[25][26]
• Prevention
  • Encourage all patients regardless of skin type to use photoprotective measures. ^[25][27]
  • Prophylactic treatment with systemic retinoids (e.g., isotretinoin, acitretin) can be considered for individuals with certain risk factors for cSCC, e.g.: ^[4]
    • History of organ transplantation
    • Genetic predisposition (e.g., xeroderma pigmentosa)
    • Autoimmune disorders (e.g., patients with psoriasis receiving PUVA treatment)
    • Multiple precancerous skin lesions (e.g., actinic keratosis)

• One-Minute Telegram 74-2023-1/3: Unclear benefit of skin cancer screening