Cutaneous Squamous Cell Carcinoma

Overview

Cutaneous squamous cell carcinoma (cSCC) is a non-melanoma (keratinocyte), epithelial skin cancer derived from the malignant transformation of normal epidermal keratinocytes (produce keratin – horny protein that makes up skin, hair, nails). It typically appears on sun-exposed skin, and although not often fatal, it can cause significant morbidity (e.g. disfigurement when involving the facial skin). Precursor lesions may include actinic keratosis or Bowen disease (SCC in situ)

Is the second-most common malignant skin tumor in humans after basal cell carcinoma (BCC). More common in males (M:F ~3:1). Typical age of presentation is 70 years. Presentation in children is associated with Xeroderma pigmentosum.

Risk Factors

• Cumulative UV exposure (as opposed to intermittent in BCC) especially in individuals with:
  • Lighter skin tone, blue eyes, blonde or red hair
  • Close geographic proximity to the equator
  • History of sunburns or recreational tanning
  • Long-term outdoor occupation
• Older age >60 years
• Male sex
• Smoking
• Previous history of SCC or any other skin cancer (BCC, melanoma)
• Presence of premalignant lesions e.g. actinic keratoses
• Chronic immunosuppression e.g. HIV, solid-organ transplant recipients, chronic lymphatic leukaemia
• Chronic inflammation or wounds e.g. Marjolin ulcer
• High-risk HPV infection for anogenital and periungual SCC
• Genetic predisposition and inherited conditions
  • Albinism
  • Xeroderma pigmentosum
  • Epidermodysplasia verruciformis
• Exposure to:
  • Ionizing radiation especially during childhood
  • Chemical carcinogens e.g. arsenic, tar, coal

Pathophysiology

• Development of SCC is associated with numerous DNA mutations in multiple somatic genes. TP53 mutations are commonly seen, leading to development of apoptosis resistance. This mutation results from UVR causing DNA damage through the creation of pyrimidine dimers. Upon subsequent UVR exposure, keratinocytes undergo colonial expansion, acquiring further defects that ultimately lead to invasive cSCC.
• Other genetic abnormalities believed to contribute to the pathogens is of cSCC include mutations in/of BCL2, RAS, COX signal transduction pathway.

Clinical Features

• Early lesions
  • Initial presentation of cSCC is usually a non-healing ulcer or abnormal growth in a sun-exposed area. This is a typical manifestation of a precursor lesion such as actinic keratosis or Bowen disease (see below). These may then develop into cSCC.
• Invasive cSCC
  • Non-healing, hyperkeratotic plaque or papule
  • May have central ulceration
  • Size ranges from few mm to several cm
  • Easily friable (bleed after minor trauma)
  • Often tender or painful
  • Grows over weeks to months

Location

• Typical location: Sun-exposed sites such as face, lips, ears, hands, forearms, lower legs
• Atypical location: Non-sun-exposed areas (especially in those with darker skin tone or chronic inflammatory skin conditions), Sub-ungual or anogenital location (associated with infection with high-risk HPV)
• Metastatic cSCC
  • Metastases can occur in approximately 3% of patients with cSCC – spread via nervous, lymphatic, vascular systems
  • Most common sites for metastasis:
    • Lymph nodes (80%)
    • Lung
    • Liver
    • Brain
    • Bone
  • Immunosuppressed individuals are at a higher risk for metastatic disease

Actinic keratosis

• Also known as solar keratosis
• Lesion found on sun-exposed areas, most commonly seen in older individuals (over 50) with light skin.
• Initially appears a small papule or plaque with sandpaper-like texture, later growing to become erythematous or brown and scaly.
• Variant presentations:
  • Actinic cheilitis – Actinic keratosis on the lower lip
  • Cutaneous horn – Benign, horn-like growth composed of keratin that may develop from pre-existing actinic keratosis or HPV warts
• If left untreated, may develop into cSCC. This is rare in solitary lesions, but the risk increases to up to 15% for those with more than 10 lesions. A tender, thickened, ulcerated or enlarging actinic keratosis is suspicious of malignant transformation to cSCC.
• Diagnosed clinically, supported by dermoscopy (findings include hyperpigmented follicular openings, brown structureless areas). In case of diagnostic uncertainty, biopsy can be performed, which would show hyperkeratosis (hyperplasia of stratum corneum), parakeratosis (retention of nuclei in stratum corneum), atypical cells in basal and squamous layers, and often an absent granular layer
• Treatment
  • Lesion-directed treatment for single or few lesions (cryosurgery, curettage, laser ablation)
  • Field-directed treatment for multiple lesions in one area (photodynamic therapy, topical agents e.g. 5-fluorouracil, imiquimod)
• Photoprotective measures should be recommended to all patients to prevent recurrence or development of additional lesions.
• Lesions may persist, regress or progress to cSCC.

Bowen disease

• Also known as intra-epidermal carcinoma (IEC) or carcinoma in situ (SCC in situ).
• Derived from squamous cells (flat epidermal cells that produce keratin), and the malignant cells remain confined to the tissue of origin (in-situ)
• Results from sun exposure. Is also often associated with HPV (high-risk subtypes 16, 18). Other risk factors include ionising radiation, arsenic exposure and immune suppression.
• Up to 50% of patients with Bowen disease have other keratinocyte skin cancers, mainly BCC.
• Lesion appears as one or more irregularly shaped plaques, with sharply defined borders. They are usually orange-red in colour but may be brown. This is usually on sun-exposed areas (face, ears, hands, lower legs) but may appear anywhere.
• Variant presentations:
  • Bowen disease of nail: Intraepidermal SCC may develop under nail resulting in a red streak (erythronychia) that may later destroy nail plate)
  • Erythroplasia of Queyrat: Bowen disease of glans penis. Etiology related to other factors such as HPV 16 and 18 rather than sun exposure, but not fully understood.
• Invasive SCC arises in about 5% of Bowen disease lesions.
• Diagnosis is usually by clinical observation supported by dermoscopy (reveals crops of rounded and coiled blood vessels). If uncertain, biopsy may be done (histology reveals full-thickness dysplasia of the epidermis)
• Treatment options include surgical excision, cryotherapy, photodynamic therapy, topical pharmacotherapy (5-FU, imiquimod)
• Patients should be advised on photoprotective measures.

Diagnosis

• Patient should first undergo a full-body skin examination to identify concurrent precancerous lesions or other skin cancers
• Dermoscopy – to support visual inspection Findings may include:
  • Ulceration without a history of trauma
  • Arborizing (branching) blood vessels
  • Features of pigmented BCC e.g. large blue-gray, ovoid nests
• Skin biopsy – for diagnostic confirmation and risk stratification
  • Possible techniques:
    • Shave biopsy – Raised lesion
    • Punch biopsy – of the most abnormal area of a large lesion. Avoid if curettage is planned for final treatment
    • Full-thickness excision all biopsy – for pigmented lesions to rule out melanoma
    • Complete excision with appropriate margins – diagnostic and therapeutic procedure for small lesions
  • Ensure adequate sample and size and depth including reticular dermis, as evidence of infiltration may only be present in the deeper layers of the tumor leading to missed diagnoses on superficial biopsies.
  • Include in pathology report:
    • Patient demographics
    • Presence of risk factors for BCC
    • Size and morphology of the lesion
    • Indicate if initial sample or repeat
  • Histological findings
    • Tumor calls appear similar to basal cells of the epidermis
    • Usually well-differentiated
    • Tumor cells align in a palisading pattern
    • Each histopthologic sub-type displays different distinguishing characteristics, e.g. presence of melanocytes in pigmented BCC
• Assessment of disease extent – for patients with high-risk features or regional, nodal /distant metastases
  • CT with IV contrast – suspected spread to lymph nodes or bone
  • PET-CT/ Ultrasound – suspected lymph node metastasis
  • MRI – suspected perineural or deep soft tissue involvement
• Staging and risk stratification
  • Since BCC so rarely metastasises, the AJCC TNM staging system has limited clinical utility.
  • BCC can be risk-stratified based on clinical and histopathologic features into:
    • High-risk BCC – lesions with any high-risk feature of BCC
      • High-risk features of BCC
        • Tumor characteristics
          • 2cm or more in size and located on trunk or extremities (excluding hands, feet, ankles, pretibia)
          • BCC of any size located in the following regions: head and neck, pretibial, hands, feet, anogenital region
          • Lesion with poorly defined/clinically indistinct borders
          • Recurrent or incompletely excised BCC
        • Histopathological features
          • Aggressive subtypes e.g morpheaform, basosquamous, infiltrating, micronodular
          • Lesions with evidence of perineural invasion
        • Patient factors
          • BCC in an immunocompromised patient
          • Tumors that develop at sites of previous radiation therapy
    • Low-risk BCC – lesions with no high-risk features of BCC
• Differential diagnoses
  • Precancerous skin lesions
    • Actinic keratosis
    • Bowen disease
    • Lentigo maligna
  • Skin and other tumors (benign and malignant)
    • Melanocytic nevi (benign)
    • Trichoepithelioma (benign)
    • Cutaneous squamous cell carcinoma
    • Melanoma
    • Cutaneous T-cell lymphoma
    • Juvenile Nasopharyngeal Angiofibroma
  • Other skin conditions
    • Psoriasis
    • Nummulite dermatitis
    • Seborrheic keratosis
    • Lichen planus
    • Molluscum contagiosum
    • Sebaceous hyperplasia

Management

Patients require multidisciplinary care: oncology, surgery, palliative care.

• Superficial therapies – for superficial low-risk BCC (higher risk of recurrence than surgery or radiation)
  • Topical pharmacotherapy – e.g. with imiquimod, 5-fluorouracil. Requires multiple sessions (imiquimod 3-5 times weekly for 6-16 weeks, 5-FU twice daily for 6-12 weeks), may result in skin irritation and inflammation, and recurrence.
  • Cryotherapy – Freezing of superficial skin lesions, usually with liquid nitrogen, resulting in a blister that crusts over and heals within weeks, leaving behind a permanent white mark. As with other superficial therapies, histological margin assessment is not feasible
  • Photodynamic therapy (PDT) – Exposure to a special light source activates administered photosensitising chemical e.g. aminolevulinic acid lotion, methyl aminolevulinate cream, causing cellular destruction. Has good cosmetic results.
• Resection – generally preferred option as it has lower recurrence rate
  • Mohs micrograph surgery – Recommended for high-risk BCC. Involves examination of carefully excised tissue under the microscope, layer by layer, to ensure complete excision. Preferred if minimal tissue excision is required, e.g. for lesions located on the eyelid. Lowest recurrence rate, however, limited availability.
  • Surgical excision – Performed for low-risk BCC, and high-risk BCC in absence of MMS. Margins should include 4mm of surrounding normal-appearing tissue, and depth up to mid-subcutaneous adipose tissue. Lesions with positive margins may require re-excision hence delayed closure should be considered until R0 resection is confirmed. Very large lesions may require flap or skin graft for repair of defect.
  • Curettage and electrodessiccation (C&E) – For low-risk BCC. Contraindicated on hair-bearing skin (risk of tumor extension into hair follicle), cosmetically sensitive areas, or for tumors extending beyond the dermis.
  • Shave removal – For low-risk BCC on the trunk or extremities. High risk of recurrence. Suture closure is not required. If subcutaneous layer is breached, surgical excision should be performed.
• Radiotherapy – when resection is contraindicated/ guided by patient preference
  • Requires multiple sessions
  • Typically for adults >60 years of age due to potential adverse effects
  • Contraindicated in individuals with genetic predisposition for skin cancers
  • Primary RT – For when resection is not feasible
  • Adjuvant RT – Consider for BCC with perineural involvement, and management of positive margins after resection.
• Systemic therapies – for locally advanced or metastatic BCC not amenable to resection or RT
  • Chemotherapy or immunotherapy – e.g cemiplimab
  • Hedgehog pathway inhibitors – e.g vismodegib, sonidegib
• Follow-up for BCC
  • Regular follow-up is crucial as patients have an increased risk of developing other skin cancers
  • 30-50% BCC patients develop another BCC within 5 years
  • Screening should occur every 6-12 months for the next 5 years, then once a year for life, except for patients with genetic predisposition (Gorlin Syndrome, xeroderma pigmentosum) who require more regular surveillance.
  • Patients should be encouraged to adhere to photoprotective measures to reduce risk of sunburn:
    • Sun avoidance when possible
    • Use of sunscreen
    • Use of protective clothing such as hats