Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Histopathologic examination should be done for all suspected cases, as many lesions, such as actinic keratosis, mimic the appearance of SCC. Surgical excision is the mainstay of treatment. Overall prognosis is excellent for completely excised lesions, but certain high-risk features may predispose to metastatic disease and poor outcomes.

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Overview

Defintion

Cutaneous squamous cell carcinoma (cSCC) is a malignant tumor of the skin arising from epidermal keratinocytes.

Epidemiology

  • The 2nd most common skin cancer after basal cell carcinoma
  • Accounts for 20% of all nonmelanoma skin cancers
  • Men > women
  • Incidence increases with age.
  • Incidence higher in people with fair skin

Risk factors

  • Exposure to ultraviolet (UV) radiation:
    • UVB: primary factor
    • UVA exposure, from tanning beds and phototherapy, also increases risk.
  • Exposure to ionizing radiation
  • Carcinogens:
    • Arsenic
    • Radon
  • Immunosuppression:
    • HIV
    • Immunosuppressive medications
  • Genetics:
    • Family history increases risk.
    • Genetic syndromes with increased risk of cSCC:
      • Xeroderma pigmentosum (mutation in repair of UV-induced DNA damage)
      • Epidermolysis bullosa (blistering skin disease with no trauma)
      • Oculocutaneous albinism (disorder of melanin synthesis)
      • Epidermodysplasia verruciformis (increased risk of HPV and cSCC)
  • Chronic inflammation:
    • Burn scars, chronic ulcers, inflammatory dermatoses, sinus tracts
    • SCC arising in a chronic wound: Marjolin’s ulcer
  • HPV infection
  • Less well-defined risk factors:
    • Smoking
    • Drugs (voriconazole, azathioprine, thiazide diuretics)
    • Dietary supplements (e.g., selenium)

Pathophysiology

Molecular pathogenesis

  • Multistep process involving accumulation of genetic and epigenetic alterations
  • Multiple genes and pathways involved:
    • TP53 (tumor suppressor gene) mutations:
      • Common early event in carcinogenesis
      • Noted in 90% of cSCCs and usually UV-related
      • Also found in actinic keratosis
    • Other mutations involve NOTCH, HRAS, and CDKN2A 
  • Multiple germline single nucleotide polymorphisms also influence cancer initiation and involve loci associated with:
    • Skin pigmentation
    • Cell-mediated immunity
    • Anti-apoptotic pathways and cellular proliferation

Cutaneous squamous cell carcinoma precursor lesions

  • Actinic keratosis:
    • Proliferation of atypical epidermal keratinocytes
    • Risk factors similar to those cSCC
    • Rate of progression to cSCC: 0.03%–20% per year
    • May spontaneously regress or may persist as actinic keratosis
  • Bowen’s disease:
    • cSCC in situ
    • Grows slowly and enlarges over many years
    • Present as erythematous or skin-colored, well-demarcated scaly patches or plaques
    • Often located in lower extremities (especially in women)
    • When penis involved, referred to as erythroplasia of Queyrat

Multiple lesions of actinic keratosis on the scalp of a 55-year-old man

Image: “Actinic keratosis of the scalp” by C. Morice, A. Acher, N. Soufir, M. Michel, F. Comoz, D. Leroy, and L. Verneuil. License: CC BY 4.0

Clinical Presentation

General clinical presentation

Occurence:

cSCC can occur on any cutaneous surface, including trunk, extremities, face, and oral and anogenital mucosa.

  • In fair-skinned individuals: most common in sun-exposed areas 
  • In dark-skinned individuals: 
    • Majority present in non–sun-exposed areas
    • Up to 40% arise from chronic scarring lesions.

Morphology:

  • Well differentiated: 
    • Indurated hyperkeratotic nodules, plaques, or papules
    • +/– ulceration
  • Poorly differentiated: 
    • Fleshy granulomatous papules or nodules (hyperkeratosis usually absent)
    • May have areas of ulceration, hemorrhage, and necrosis

Color: varies from flesh-colored to erythematous

Symptoms:

  • Commonly asymptomatic, but may present with pain and pruritus
  • Paresthesias may occur with high-risk cSCCs, indicating local perineural invasion.

Clinical variants

Marjolin’s ulcer:

  • Appears as a slow-growing nonhealing lesion/ulcer 
  • SCC associated with chronic wounds are aggressive.
  • In areas of chronically irritated epithelium:
    • Burn scars
    • Nonhealing ulcers (e.g., venous ulcers) 

Keratoacanthoma:

  • Well-differentiated cSCC (sometimes classified as a separate entity)
  • Dome-shaped or crateriform nodules with a central keratotic core

Verrucous carcinoma:

  • Present as large cauliflower-like warts
  • Sites of lesions: oral, anogenital, or plantar lesions

SCC of the lip: nodule or plaque usually on the lower lip

Oral SCC: ulcer, nodule or plaque in the oral cavity

Diagnosis and Staging

Diagnostic approach

History:

  • Excessive sun exposure (occupational or recreational)
  • Radiation exposure
  • Family history, genetic disorders
  • HIV, immunosuppressive medications
  • History of other skin cancers or papillomas
  • Chronic poorly healing wounds (for Marjolin’s ulcers)

Physical exam:

  • Thorough skin examination should be performed to evaluate for concomitant lesions.
  • Look for lymphadenopathy, which may indicate advanced disease.

Dermoscopy: 

  • Bowen’s disease (cSCC in situ): surface scales with red-yellowish background
  • Invasive SCC:
    • White and structureless areas
    • Hairpin and linear-irregular vessels

Biopsy:

  • Must be performed for definitive diagnosis
  • Techniques: shave, punch, or excisional
  • If invasive SCC is suspected, biopsy should go down to the level of the midreticular dermis, regardless of technique.
  • SCC in situ histopathology:
    • Atypical keratinocytes with no infiltration of the dermis
    • Usually with thickened epidermis and hyperkeratosis of the stratum corneum
  • Invasive SCC histopathology: 
    • Atypical keratinocytes with basement membrane and dermis infiltration
      • Well differentiated: keratinocytes appear with close-to-normal nuclei and abundant cytoplasm
      • Poorly differentiated: anaplastic keratinocytes, noted to have more nuclear atypia with less cytoplasm; numerous mitoses 
    • Perineural infiltration signifies poorly differentiated SCC with metastatic potential.
    • Immunohistochemical staining for poorly differentiated (anaplastic) lesions: positive for cytokeratin

Invasive SCC:
Well-differentiated lesions showing prominent keratinization structures (keratin pearls)

Image: “Micrograph of well-differentiated and invasive squamous-cell carcinoma” by Valerie R. Yanofsky, Stephen E. Mercer, and Robert G. Phelps. License: CC BY 4.0

Evaluation of metastasis

  • Rate of metastasis: 2%–5%
  • Lymph node evaluation:
    • Lymph nodes are the most common metastatic site:
      • Lip and anterior mouth: submental lymph nodes
      • Nose and cheek: submandibular lymph nodes
      • External ear: posterior auricular lymph nodes
      • Anterior scalp, forehead, temple: parotid lymph nodes
      • Posterior scalp: occipital lymph nodes
    • Palpable lymph nodes evaluated via the following options:
      • Fine-needle aspiration
      • Surgical removal and pathologic examination
    • Imaging options (done if with lymph nodes positive):
      • CT 
      • MRI
  • If there are no palpable lymph nodes, consider imaging if the following high-risk features are present
    • Tumor diameter:
      • ≥ 6 mm: central face (mask area), ears, hands, feet
      • ≥ 10 mm: other face areas, pretibia
      • ≥ 20 mm: rest of trunk and extremities
    • Poorly differentiated histology
    • Perineural and/or deep invasion
    • Immunosuppressed patient
    • Site of previous radiation, chronic wounds/scars
    • Recurrent tumors
  • Other sites of metastasis:
    • Lungs
    • Liver
    • Brain
    • Bones

Staging

American Joint Commission on Cancer 2018 TNM system:

Only applicable to SCC of the head and neck area (lip, ear, face, scalp, and neck).

  • Stage 0: cancer involves only the epidermis (in situ)
  • Stage I: 
    • Cancer is not large (≤ 2 cm)
    • No spread to the lymph nodes or other organs
  • Stage II: 
    • Cancer is large (>2 cm but ≤ 4 cm). 
    • No spread to lymph nodes or other organs
  • Stage III: 
    • Cancer > 4 cm or cancer of any size with deep, perineural, or minor bone invasion and/or to 1 ipsilateral lymph node (no extranodal extension)
    • No spread to other organs
  • Stage IV: lesion of any size and has spread to other organs (distant metastasis

Brigham and Women’s Hospital (BWH) staging:

  • Alternative tumor staging system based on presence of high-risk factors
  • Can be applied to SCC in all body sites

Management

Treatment approach

Standard surgical excision:

  • 1st-line treatment
  • Negative margins need to be achieved.
  • Generally with margins of 4–6 mm (low-risk lesions) or > 6 mm (high-risk lesions)

Mohs micrographic surgery:

  • Used for cosmetically sensitive areas where procedure could be disfiguring
  • Can also be used for reexcision if original margins were positive

Alternatives to surgery (not for high-risk lesions):

  • Electrodesiccation and curettage
  • Cryotherapy
  • Topical fluorouracil and photodynamic therapy are additional options for Bowen’s disease.

Radiation:

  • Rarely used as primary treatment
  • Adjunctive treatment for high-risk lesions
  • Salvage therapy after excision with positive margins

Systemic treatment:

  • Immunotherapy: 
    • For metastasis, locally advanced disease not amenable to surgery or radiotherapy
    • Programmed death-ligand 1 (PD-L1) or PD-L1 inhibitor: 
      • Cemiplimab
      • Pembrolizumab 
  • Cisplatin-based chemotherapy and/or epidermal growth factor receptor (EGFR) inhibitor (cetuximab): considered for advanced SCC due to immunosuppression for organ transplantation 

Prognosis

  • Overall 5-year cure rate is 90%.
  • 95% of recurrences occur within 5 years.
  • If distant metastases are present, 5-year survival is < 10%.

Differential Diagnosis

  • Seborrheic keratosis: benign neoplasm consisting of immature keratinocytes occurring commonly in the elderly. Seborrheic keratosis is well demarcated, waxy, and has a stuck-on appearance. 
  • Actinic keratosis: precancerous lesion affecting sun-exposed areas (e.g., scalp and hands) in elderly people. Actinic keratosis appears as a scaly, slightly elevated lesion that can eventually progress to invasive SCC.
  • Inflammatory skin disorders: psoriasis, eczema, pyoderma gangrenosum, venous stasis ulcers. All of these disorders can present with scaly pink or flesh-colored plaques, patches, and nodules.
  • Other skin malignancies: Basal cell carcinoma is the most important differential diagnosis. Basal cell carcinoma is the most common skin cancer arising from the basal cell layer of the epidermis. Most patients present with a pearly nodular skin lesion with telangiectasia that grows slowly. Other skin cancers that can appear similar to SCC are amelanotic melanoma, Merkel’s cell carcinoma, and atypical fibroxanthoma.

References

  1. Aasi S. Z., Hong A. M. (2020). Treatment and prognosis of low-risk cutaneous squamous cell carcinoma. UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/treatment-and-prognosis-of-low-risk-cutaneous-squamous-cell-carcinoma
  2. DeSimone J. A., Karia P. S., Hong A. M., Ruiz E. S., Jambusaria-Pahlajani A. (2020). Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma.UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/recognition-and-management-of-high-risk-aggressive-cutaneous-squamous-cell-carcinoma
  3. Lim J. L., Asgari M. (2020). Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis. UpToDate. Retrieved January 18, 2021, from https://www.uptodate.com/contents/cutaneous-squamous-cell-carcinoma-cscc-clinical-features-and-diagnosis
  4. Lim J. L., Asgari M. (2020). Cutaneous squamous cell carcinoma: Epidemiology, risk factors, and molecular pathogenesis. Retrieved January 18, 2021, from https://www.uptodate.com/contents/cutaneous-squamous-cell-carcinoma-epidemiology-risk-factors-and-molecular-pathogenesis
  5. Lonsdorf A. S., Hadaschik E.N. (2019). Squamous cell carcinoma and keratoacanthoma. Kang S, et al. (Ed.), Fitzpatrick’s Dermatology, 9th ed. McGraw-Hill.
  6. Martins, R. (2020). Systemic treatment of advanced cutaneous squamous and basal cell carcinomas. UpToDate. Retrieved Feb 4, 2021, from https://www.uptodate.com/contents/systemic-treatment-of-advanced-cutaneous-squamous-and-basal-cell-carcinomas
  7. Sarin, K. Y., Lin, Y., Daneshjou, R. et al. (2020). Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma. Nat Commun 11, 820. https://doi.org/10.1038/s41467-020-14594-5
  8. Turnbull N. (2014). Squamous cell carcinoma pathology. https://www.dermnetnz.org/topics/squamous-cell-carcinoma-pathology

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