Squamous cell carcinoma

Introduction

Squamous cell carcinoma (SCC) is the second most common skin cancer, arising from keratinocytes of the epidermis. It can range from slow-growing, localized tumors to aggressive cancers with metastatic potential. Unlike basal cell carcinoma (BCC), SCC has a higher risk of spreading, particularly in immunosuppressed patients or high-risk sites like the lips, ears, and genitalia.

SCC primarily develops due to chronic sun exposure, but it can also arise from pre-malignant lesions, chronic wounds, or viral infections (HPV-related SCCs). Early detection and treatment are essential to prevent complications.

Epidemiology and Risk Factors

Prevalence:

• Second most common skin cancer worldwide (~20% of all skin cancers).
• Most common in fair-skinned individuals >50 years old.
• Higher incidence in Australia due to UV exposure.

Risk Factors for SCC:

Category	Examples
UV Radiation (Primary Cause)	Chronic sun exposure, outdoor work, tanning beds
Fair Skin Phenotype	Fitzpatrick skin types I & II (blonde, red hair, blue eyes)
Pre-Malignant Lesions	Actinic keratosis, Bowen’s disease
Immunosuppression	HIV/AIDS, organ transplant recipients, chronic steroid use
Chronic Inflammation & Scars	Burn scars, non-healing ulcers (Marjolin’s ulcer), radiation dermatitis
Human Papillomavirus (HPV)	SCC of genitalia, periungual SCC (fingernails, toenails)
Tobacco & Alcohol Use	Increased risk for SCC of the lip and oral mucosa
Arsenic & Chemical Exposure	Increased risk in mining, pesticides, occupational exposure

Pathophysiology

1. UV-Induced DNA Damage (Primary Pathway)
   • UVB radiation causes mutations in the p53 tumor suppressor gene.
   • Leads to uncontrolled keratinocyte proliferation and dysplasia.
2. Precursor Lesions Progress to SCC
   • Actinic keratosis (precancerous lesion) → SCC in situ (Bowen’s disease) → Invasive SCC.
   • HPV-driven SCC (genital/periungual SCC) arises via E6 and E7 oncogene activation.
3. Potential for Local Invasion & Metastasis
   • SCC can invade the dermis, muscle, and bone.
   • High-risk locations (ears, lips, genitalia) and immunosuppressed patients have a greater risk of metastasis.

Clinical Features

1. Types of SCC and Their Features

Type	Key Features	Common Locations
Cutaneous SCC (Most Common, ~90%)	Scaly, crusted nodule or plaque, ulceration, non-healing wound	Face, scalp, ears, hands
Bowen’s Disease (SCC in situ)	Well-defined red scaly plaque, does not invade the dermis	Trunk, extremities
Keratoacanthoma (KA-Type SCC)	Rapidly growing, dome-shaped lesion with central keratin plug	Sun-exposed skin (face, arms)
Mucosal SCC (Oral, Lip, Genital SCC)	Ulcerative, non-healing lesion, associated with HPV, smoking, alcohol	Lips, oral mucosa, vulva, penis
Periungual SCC	Warty, ulcerated lesion near fingernails/toenails, linked to HPV	Nail bed, cuticles

2. Common Symptoms

• Non-healing, scaly, or crusted lesion that may bleed easily.
• Pain, tenderness, or itching (especially if ulcerated).
• Firm, indurated, raised edges with central ulceration (advanced cases).
• May appear as an exophytic (outward-growing) mass.

Diagnosis

1. Clinical Diagnosis (Most Cases)

• Non-healing, scaly, erythematous lesion with or without ulceration.
• History of chronic sun exposure, immunosuppression, or precursor lesions.

2. Dermoscopy (To Aid in Diagnosis)

• Glomerular vessels (clustered, looped capillaries).
• Scales and white circles (hyperkeratosis and follicular plugging).
• Yellowish keratin masses (keratoacanthoma-type SCC).

3. Skin Biopsy (Definitive Diagnosis)

• Punch or shave biopsy for small lesions.
• Excisional biopsy for larger or high-risk lesions.
• Histopathology Findings:
  • Atypical keratinocytes invading the dermis.
  • Dysplastic, pleomorphic nuclei with keratin pearl formation.
  • Loss of normal maturation and polarity in keratinocytes.

4. Imaging (For High-Risk or Suspected Metastatic SCC)

• MRI or CT scan – If deep invasion, perineural spread, or bony involvement.
• PET scan or lymph node ultrasound – If metastatic spread is suspected.

5. Differential Diagnosis

Condition	Key Differences
Actinic keratosis	Pre-malignant, rough/scaly lesion, no dermal invasion
Basal cell carcinoma (BCC)	Pearly, slow-growing, less likely to ulcerate
Verrucous carcinoma	Slow-growing, warty lesion, HPV-associated
Malignant melanoma	Irregular borders, multiple colors, rapid growth

Management and Treatment

1. First-Line Treatment (For Localized SCC)

Treatment	Indications	Cure Rate
Surgical Excision (Gold Standard)	Most SCCs, low or high-risk lesions	>95%
Mohs Micrographic Surgery	High-risk SCCs (face, hands, perineum, recurrent tumors)	98–99%
Curettage & Electrodessication	Small, well-defined, low-risk SCCs	90%

2. Non-Surgical Treatment (For Superficial or Inoperable SCCs)

Treatment	When to Use
Topical 5-Fluorouracil (5-FU)	SCC in situ (Bowen’s disease)
Imiquimod (Immune Modulator)	Superficial SCC
Photodynamic Therapy (PDT)	Superficial, low-risk SCC
Radiation Therapy	For inoperable SCC or elderly patients

3. Systemic Therapy (For Advanced or Metastatic SCC)

• Cisplatin-Based Chemotherapy – For nodal/metastatic SCC.
• Immunotherapy (Cemiplimab, Pembrolizumab) – FDA-approved PD-1 inhibitors for advanced SCC.

Complications

• Local tissue destruction (cartilage, bone involvement).
• Perineural invasion → facial paralysis, nerve pain.
• Regional lymph node spread (high-risk areas: lips, ears, scalp, genitalia).
• Distant metastasis (lungs, liver, brain in <5% of cases).

Prognosis and Follow-Up

• Low-risk SCC (localized, well-differentiated): Cure rate >95% with early treatment.
• High-risk SCC (perineural invasion, lymph node spread): Higher recurrence and metastasis risk (~5–10%).
• Follow-up every 3–6 months for 2 years, then annually.

Conclusion

Squamous cell carcinoma is a common, sun-induced skin cancer with higher metastatic potential than basal cell carcinoma. Early detection, surgical excision, and sun protection are key to preventing recurrence and metastasis. High-risk SCCs require close follow-up and aggressive management to reduce complications.