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Squamous Cell Carcinoma, Cutaneous

BASICS

  • Definition:
  • Second most common nonmelanoma skin cancer after basal cell carcinoma.
  • Arises from keratinocytes in sun-damaged skin; may also develop in chronic wounds, scars, or areas of immunosuppression.

EPIDEMIOLOGY

  • Most common malignancy worldwide (nonmelanoma).
  • Historically thought to account for 20% of nonmelanoma skin cancers, but incidence increasing.
  • Average age: ~60 years; more common in men.
  • Incidence rises closer to equator or at higher altitude.

ETIOLOGY & PATHOPHYSIOLOGY

  • Genetics:
  • Associated with hereditary syndromes: xeroderma pigmentosum, oculocutaneous albinism, epidermodysplasia verruciformis.
  • Mutated genes: TP53 (most common), CDKN2A, NOTCH1, Ras.
  • Risk Factors:
  • Elderly white individuals, male sex, increasing age, preexisting actinic keratosis (AK), chronic UV exposure.
  • Immunosuppression (transplant, HIV/AIDS, lymphoma/leukemia).
  • Chronic skin disease: burns, hidradenitis suppurativa, osteomyelitis, discoid lupus, lichen planus/sclerosis.
  • Inherited conditions: albinism, epidermolysis bullosa.
  • Ionizing radiation, arsenic exposure, chronic ulcers.
  • HPV infection (types 6, 11, 16, 18), BRAF inhibitors (vemurafenib, dabrafenib).
  • Commonly Associated Conditions:
  • AK (precursor), Bowen disease, erythroplasia of Queyrat.

GENERAL PREVENTION

  • Sun protection: sunscreen, hats, UV-protective clothing.
  • Vitamin B3 (nicotinamide) may protect DNA against UV-induced damage.

DIAGNOSIS

  • Gold standard: Histopathology via punch or shave biopsy.
  • Dermoscopy: Improves accuracy.
  • Physical Exam:
  • Lesions on chronically sun-exposed sites (face, ears, scalp, forearms, hands).
  • Elderly women: often on legs and other exposed areas.
  • African Americans: equal frequency in sun-exposed and unexposed areas.
  • Lesion features:
  • Slow-growing, firm, hyperkeratotic papules/nodules/plaques.
  • May be asymptomatic or have bleeding, pain, tenderness.
  • Surfaces may be smooth, verrucous, papillomatous; may ulcerate, erode, crust, or scale.
  • Colors: red, brown, tan, pearly.
  • Clinical variants:
    • Bowen disease (in situ): scaly psoriatic-like plaque.
    • Invasive SCC: raised, firm papule/nodule/plaque, variable surface.
    • Cutaneous horn: thick, hard keratinization.
    • Erythroplasia of Queyrat: velvety red plaques on glans penis.
    • Subungual SCC: hyperkeratotic periungual/nail lesions.
    • Marjolin ulcer: SCC arising in a scar or chronic ulcer.
    • HPV-associated SCC: warty growths in genital/perianal areas.
    • Verrucous carcinoma: cauliflower-like nodules/plaques.
    • Basaloid SCC: men, ages 40–70.
  • Differential Diagnosis:
  • Actinic keratosis, basal cell carcinoma.

DIAGNOSTIC TESTS & INTERPRETATION

  • Biopsy: Shows pleomorphic, hyperchromatic squamous cells, keratinocyte mitoses, squamous pearls, full-thickness atypia.
  • High-risk features for recurrence/metastasis:
  • Tumor diameter >2 cm
  • Perineural involvement >0.1 mm
  • Poor differentiation
  • Recurrent or previously treated SCC
  • SCC in scars

  • Immunosuppression

  • Staging:

  • AJCC (8th edition), Brigham and Women's staging (T2b or higher = high risk).

TREATMENT

  • First Line:
  • Complete surgical excision with histopathologic margin control.
  • Mohs micrographic surgery (MMS): Gold standard for high-risk or recurrent tumors.
  • Other options (low-risk): Wide local excision, electrodesiccation, curettage, cryotherapy.

  • Radiation: For inoperable tumors, bleeding disorders, surgical contraindications.

  • Second Line / Advanced Disease:

  • Monoclonal antibodies (cetuximab, panitumumab)
  • Tyrosine kinase inhibitors (erlotinib)
  • Chemotherapy (methotrexate, bleomycin, doxorubicin, cisplatin)
  • Oral retinoids to reduce AK/SCC incidence

SURGERY/OTHER PROCEDURES

  • Radiation therapy: For poor surgical candidates or inoperable locations.
  • Side effects: malaise, nausea, erythema, telangiectasia, hypopigmentation, atrophy, necrosis, radiation-induced malignancy.

ONGOING CARE & PROGNOSIS

  • Follow-up:
  • High-risk SCC: complete skin & lymph node exam every 2–6 months, then every 6–12 months (next 3 years), then annually.

  • With regional disease: exam every 1–3 months initially, then spacing out as above.

  • Recurrence/Metastasis risk:

  • 7–80% will recur/metastasize within 2 years (95% within 5 years).
  • 30–50% develop a second skin cancer within 5 years.
  • Poor prognosis with tumor recurrence, diameter ≥2 cm, thickness >2 mm, poor differentiation, deep invasion, perineural involvement ≥0.1 mm, high-risk sites (eye, lip, mask areas, hands, feet, genitalia).
  • MMS cure rates: 97% (primary), 94% (recurrent).

  • Distant metastasis: 15% (brain, lungs, liver, skin, bone).

  • Survival rates:

  • Distant metastasis: 10-year survival <10%
  • Regional lymph nodes: 10-year survival <20%

COMPLICATIONS

  • Local recurrence
  • Metastasis (nodal, distant)

ICD-10

  • C44.92: SCC of skin, unspecified
  • C44.320: SCC of skin, unspecified parts of face
  • C44.42: SCC of skin of scalp and neck

CLINICAL PEARLS

  • Cutaneous SCC: strongly associated with UV exposure, immunosuppression.
  • Head and neck: most common sites.
  • Mohs micrographic surgery: highest cure rates for high-risk lesions.
  • Staging is essential for high-risk SCC.