Squamous Cell Carcinoma (SCC)

Definition

• Fitzpatrick's Dermatology, Vol. 1-2

Etiology and Pathophysiology

1. Ultraviolet Radiation (Primary Risk Factor)

• Both UVB and UVA are carcinogenic, with a strong dose-response relationship
• UVB causes direct UV signature mutations: characteristic C→T and CC→TT dipyrimidine transitions in TP53 and other genes
• UVA contributes via photooxidative stress and reactive oxygen species
• UVR also exerts immunosuppressive effects: depletes Langerhans cells, impairs antigen presentation, expands regulatory T cells, and shifts the response toward Th2

2. Molecular Pathogenesis

3. Other Risk Factors

• Genetic predisposition: Skin phototypes I/II (fair skin); MC1R variants; oculocutaneous albinism (1000-fold increased risk in Black albinos)
• Genodermatoses: Xeroderma pigmentosum (XPA-G, XP-V defects), Recessive dystrophic epidermolysis bullosa (>90% cumulative SCC risk by age 55)
• Immunosuppression: Organ transplant recipients (OTRs) have markedly elevated risk; SCC accounts for >60% of skin cancer deaths in OTRs
• HPV: Certain HPV types inhibit p53-mediated checkpoints via E6/E7 oncoproteins (especially relevant in anogenital SCC and oropharyngeal SCC)
• Skin damage: Chronic scars/burns, radiation exposure, chronic inflammation (Marjolin's ulcer concept)
• Chemical carcinogens: Arsenic, polycyclic aromatic hydrocarbons, tobacco (oral SCC)

Clinical Features

• A diffuse, non-healing, crusted or ulcerated lesion
• A firm, indurated nodule or plaque, often with surrounding erythema
• May arise at the base of an actinic keratosis (AK) - the principal precursor lesion
• Lesions may be multifocal

SCC in Situ (Bowen's Disease)

• Severely dysplastic lesion confined to the epidermis (has not yet invaded the dermis)
• Presents as a well-demarcated, erythematous, scaly plaque
• Treated similarly to invasive SCC; excision is rarely required unless concern for invasion

Histopathology

• Well-differentiated (Grade 1): Minimal pleomorphism, prominent keratinization, parakeratosis, individual cell dyskeratosis, horn (keratin) pearl formation
• Poorly differentiated (Grade 3-4): Pleomorphic nuclei, high atypia, frequent mitoses, minimal keratinization

Key Histologic Variants

Head & Neck SCC - Special Histology (Goldman-Cecil)

• HPV-negative (environmental): Well- to poorly differentiated; keratin pearls present
• HPV-positive (oropharyngeal): Poorly differentiated or basaloid; no keratin pearls; diagnosed by p16 immunohistochemistry (>70% diffuse nuclear/cytoplasmic staining = HPV-positive); confirms functionally relevant E7 oncoprotein

High-Risk Features (NCCN Criteria)

1. Diameter >2 cm
2. Depth of invasion below subcutaneous adipose
3. Perineural invasion
4. Immunosuppression (organ transplant recipients)

Staging (Head & Neck SCC)

• Complete head/neck examination with fiberoptic endoscopy
• CT or MRI for locoregional staging
• Chest imaging (synchronous pulmonary primary in <10%)
• HPV status determination for all oropharyngeal SCC (alters both staging and prognosis)
• Goldman-Cecil Medicine, International Edition

Treatment

1. Surgical Excision (Primary Treatment)

• Standard excision with at least 5 mm clear margins for invasive SCC
• Mohs micrographic surgery is preferred for high-risk tumors (H-zone of face, >2 cm, aggressive histology, perineural invasion, recurrent tumors)
  • Recurrence rates: Standard excision 8.1% (primary) / 23.3% (recurrent); Mohs surgery 3.1% / 10.0%
  • Mohs provides 3-4x lower recurrence rate than standard excision (supported by meta-analyses of >10,000 patients)

2. Electrodessication and Curettage (ED&C)

• Acceptable for early, small, low-risk lesions
• Not appropriate for high-risk tumors

3. Cryotherapy

• For small, early lesions in good-risk anatomic locations
• Post-treatment residual lesions after treating actinic changes should be biopsied

4. Radiation Therapy

• Used for adjuvant treatment of high-risk or node-positive disease
• Option for patients not surgical candidates

5. Chemotherapy (Advanced/Metastatic)

• Platinum-based regimens, 5-fluorouracil/capecitabine, or methotrexate monotherapy
• Limited effect on overall survival; frequently restricted by comorbidities

6. Targeted Therapy

• Cetuximab (anti-EGFR antibody): 29% response rate in unresectable SCC as first-line monotherapy (Phase II trial); also used as radiosensitizer
• Erlotinib/Gefitinib (EGFR small-molecule inhibitors): off-label options beyond radiotherapy and conventional chemotherapy
• mTOR inhibitors (sirolimus): Reduce secondary SCC incidence in OTRs

7. Immunotherapy

• PD-1/PD-L1 checkpoint inhibitors: Emerging evidence; PD-L1 overexpression in keratinocytes accelerates SCC formation in preclinical models; checkpoint blockade has shown antitumor responses in unresectable SCC
• (Note: Cemiplimab/Libtayo was FDA-approved for advanced cSCC after this textbook's publication - now first-line for unresectable/metastatic cutaneous SCC)

Metastasis and Prognosis

• Overall 5-year metastatic rate: ~5% for all-comers (85% of metastases are nodal)
• Certain high-risk subgroups: metastatic rates up to 30%
• Unresectable SCC: median overall survival only 10.9 months
• OTRs: >60% of skin cancer deaths; 5% disease-specific mortality from SCC
• Local recurrence often precedes distant metastasis and signals aggressive behavior

Follow-Up Schedule

SCC at Other Sites (Brief Summary)

• Fitzpatrick's Dermatology, 8th ed., Vol. 1-2 - Chapters 112, 204
• Goldman-Cecil Medicine, International Edition, 2-Volume Set - Chapter 176
• Pfenninger and Fowler's Procedures for Primary Care, 3rd ed. - Chapter 12
• Textbook of Family Medicine, 9th ed.