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Squamous cell carcinoma

Section: Skin and soft tissue Sub-section: Skin cancer Curriculum: Curriculum, page 52

Definition

  • Malignancy of epidermal keratinocytes

Incidence

  • Middle age – elderly
  • 1/5 of non-melanoma skin cancers
  • 50% chance of second in SCC in 5 yrs.

Aetiology/Risk Factors

  • Sunlight most common cause in Fair skin
    • UV-B (B = Bad)
  • Actinic Keratoses (proliferation of keratin cells in basal layer)
  • Immunosuppression (50% increased risk)
  • Smoking → Oral SCC
  • Chronic scars / Ulcers
  • Infections:
    • Chronic Granulomas (e.g. TB of the skin, Syphilis)
    • Viral – HPV/ EBV
  • Occupational exposures:
    • Contact with Tars, Hydrocarbons, Arsenic
    • Chemical & thermal burns
  • Exposure to ionizing radiation / Radiotherapy
  • Drugs - azathioprine, hydrochlorothiazide, BRAF inhibitors (very common
  • Genetic predisposition:

Pathogenesis

  • Genes included are - TP53 and NOTCH pathway

Classification

  • High Risk SCC
    • Location on the ear, vermillion of the lip, central face, hands, feet, genitals.
    • Histology
      • Depth > 6mm, or Clark 4/5
      • Poorly Differentiated
      • Subtype –Desmoplastic, carcinosarcomatous, Adenosquamous type
      • LVI/Perineural Invasion (>0.1mm nerve)
    • Recurrent tumours
    • Immunosuppression
    • Site of previous radiation treatment or chronic inflammation (Marjolin ulcer)
    • Rapidly growing
  • Low risk
    • Diameter < 2cm.
    • Well or moderately differentiated tumour
    • None of the above features.

Clinical Classification

Invasive SCC

  • Dysplastic keratinocytes which are full thickness and invade the basement membrane to involve the dermis.
  • Can be well, moderately, or poorly differentiated.

Keratotic Horn

  • Hard keratin accumulation
  • Arise from benign, pre-malignant or malignant SCC

Keratoacanthoma

  • May be indistinguishable from well-differentiated squamous cell carcinoma
  • May spontaneously regress
  • Arise from hair follicle cells

Verrucous Carcinoma

  • SCC induced by HPV
  • Slow growing
  • Usually occurs on the sole of the foot, but can be Anogenital (known as Giant Condyloma acuminatum of Buschke-Lowenstein)
    • Can be on the plantar foot (Epithelioma cuniculatum)
  • Fungating
    • Invade deeply & extensively
  • But rarely metastasis
  • Surgery is mainstay of treatment
  • Can progress to high grade SCC after RT
  • Strongly associated with
    • Smoking
    • EtOH

Marjolin ulcer

  • SCC which arises from sites of chronic wounds or scars.
  • Malignant transformation is very slow, with average latency of 30 years.

Lymphoepithelioma-like carcinoma of the skin

  • Very rare, indolent, malignant skin tumour of epithelial origin.
  • Resembles nasopharyngeal SCC

Bowen’s disease

  • SCC in-situ = Pre-malignant
  • Pathology
    • Diagnosed when keratinocyte dysplasia is full thickness of the epidermis without infiltration into the dermis (through the basement membrane)
    • Keratinocytes show pleomorphism, hyperchromatic nuclei, and nuclear mitosis.
    • Frequently there is associated thickening of the epidermis.
  • Clinical
    • Reddened area with plaque like thickening
    • Can cover large areas
    • Rough, scaly, erythematous macules which develop on sun-damaged skin and demonstrate keratinocyte atypia
  • Progression
    • The rate of transformation to an SCC is low - about 1% per year
    • Progression to invasion 15-20 years (1:1000 lesion/year)
    • 5% show invasion at time of removal
  • Bowen’s disease of the penis
    • Erythroplasia of Queyrat

Bowenoid papulosis

  • Premalignant lesion which arise from genital wards - associated with HPV 16 (and others) infection

Clinical Presentation

  • Sun exposed skin – nose, ears, lips, forehead
  • Raised edge, often symmetrical with central keratin
  • Key to diagnosis = Presence of surface keratin
  • Occasionally inflammatory appearance – poor differentiation
  • Forms ulcers / fungating lesions with heaped-up edges
  • 75% on head; 15% hands
  • Lesion grows for 1-2mths before a pt complains of it
  • Grows faster than BCC
  • SCC arising in a burn (or chronic wound)
  • Lymphadenopathy may be
    • Reactive
    • Due to metastasis

Pathology

  • UV radiation causes damage 2 ways:
    • Direct carcinogenic effect on epidermal keratinocytes
    • Depression of cutaneous immune surveillance
      • p53 mutation in 90% SCC
  • Arise from keratinocytes due to mutations during their progression from the basal to the cornified layer
  • Most SCCs arise from Actinic keratosis
  • 3-5% metastasize via lymphatics
    • To LN’s, lungs, bone, or brain
  • High risk lesions – 10-15% metastasize to LN

Microscopic Appearance

  • Large cells with
    • Intercellular bridges & keratin pearls
  • Normal layering lost
    • Replacement by atypical cells
    • Can extend into hair follicles
  • Cellular atypia seen in all layers of epidermis
    • Tumour cells infiltrate epidermis, dermis & adjacent tissues

Workup

  • Full history
  • Examine local LNs and do full skin check
  • Excision biopsy for diagnosis
  • Indication for further imaging
    • Patients with high risk SCC’s
    • Patients with involved nodes

Evaluation of nodal metastasis

  • Patients with palpable nodes should undergo FNA or lymph node biopsy.
  • Generally if the FNA is negative - you should excise the node to ensure it isn’t involved (i.e. FNA has relatively high false negatives)
  • CT is the modality of choice to evaluate clinically negative nodal basins.
  • MRI is also good - but more expensive.

Evaluation of distant metastasis

  • Most common sites are lung, liver, brain and bone.
  • Modality of choice is CT
  • PET-CT in New Zealand - “Staging or restaging of locally advanced cutaneous Squamous cell carcinoma for patients who are otherwise suitable for locoregional therapy with curative intent”

Staging

T Staging

  • pT1: ≤ 20mm in maximum clinical dimension
  • pT2: > 20mm to ≤ 40mm
  • pT3: > 40mm or minimal cortical/marrow invasion
  • pT4a: Tumour with gross cortical/marrow invasion
  • pT4b: Tumour with axial skeleton/skull base/foraminal invasion

N Staging

  • N0: No regional LN mets
  • N1: Mets in a single ipsilateral LN ≤ 3cm and no Extranodal Extension (ENE)
  • N2
    • A - Mets in a single ipsilateral LN > 3cm but < 6cm and ENE -ve
    • B - Mets in multiple ipsilateral LN, < 6cm, ENE -ve
    • C - Bilateral or contralateral LN, < 6cm, ENE -ve
  • N3:
    • A - Mets in a LN > 6cm and ENE -ve
    • B - Mets in any nodes and clinically overt ENE +ve

M Staging

  • M0: No distant mets
  • M1: Distant mets

Staging by TNM

Stage

  • Stage 1
    • T1
  • Stage 2
    • T2
  • Stage 3
    • T3
    • N1, T1-T3
  • Stage 4
    • T4
    • N2-N3

Management

Treatment of low risk SCC

  • Surgical
    • Standard excision - should have 5mm clinical margin. Need to take excise down to subcutaneous fat.

    • 1mm microscopic margin is acceptable.

      • Mohs surgery - can be utilized as a skin-sparing technique where margin of 4mm would lead to a poor cosmetic outcome.
  • Other options
    • These options do not allow margin evaluation - should only be used for small low risk lesions in low risk sites.
      • Curettage and electrodessication
      • Cryosurgery - freezes tumours. Occurs from formation of intra and extracellular ice crystals, hypertonicity, and disruption of the phospholipid membrane.
  • Treatment of multiple low risk lesions
    • Commonly occurs on areas of sun damaged skin where there are multiple actinic keratosis.
      • Options include
  • Treatment of Bowen’s disease
    • Surgery - 4mm margin
    • Topical
      • Topical 5-Fluorouracil 5% - BD for 4 weeks.
      • Imiquimod
        • Stimulate an immune response thus area will become inflammed - this indicates the cream is likely to be effective.
      • Cryotherapy
      • Currettage and electrodessication

Treatment of high risk SCC

  • Surgery
    • The recommended modality is MOHS surgery
    • Standard excision is commonly performed but is inferior (higher recurrence rates)
    • Treatment which doesn’t allow margin assessment is contraindicated (i.e. cryosurgery and curretage).
    • Should aim for >6mm clinical margin
    • A histological margin of >1mm is adequate.
  • Management of nodal disease
    • Aggressive surgical resection is primary treatment modality.
    • If 2+ positive nodes, or one node >3cm, any node with extracapsular extension - patient should received adjuvant radiotherapy (N2 or N3)
  • Radiation
    • May be recommended as definitive treatment, adjunctive, or palliative treatment where complete surgical removal is not possible
    • Indications for adjuvant radiation
      • Tumours with positive surgical margins not amendable to further surgery
      • Tumours with extensive PNI or large nerve involvement.
      • Multi-focal tumour spread
      • Presence of microsatellite tumours
      • Lymph node involvement (N2 or N3)
      • Massive local extension or intracranial involvement.
    • Contraindications:
  • Systemic therapies
    • Targeted
      • PD-1 inhibitors like Pembrolizumab are highly efficacious for locally advanced and metastatic SCC.
      • Anti-EGFR
        • Cetuximab is commonly used as immunotherapy.
    • Chemotherapy
    • Other adjunctive treatments
      • Oral retinoids such as isotretinoin are commonly used

Unresectable Disease

  • Platin-based Cisplatin with Radiotherapy
  • Targeted therapy: Cetuximab (Epidermal Growth Factor Inhibitor) +/- Chemo +/- Radiotherapy
  • Immunotherapy – PD-1 Inhibitor
    • Cemiplimab (Australia)

Prognosis/Natural Hx

  • Need to re-excise if positive margins
    • Recurrence rate ≈ 50% if excision margin involved
  • Tumour thickness correlates well with biologic behaviour
    • Tumours that recur locally are usually ≥4mm
  • Rare for tumour < 4mm to metastasize
    • Tumours > 10mm thick → Mets frequent
  • If LN positive disease → 15% 10YS

Recurrence

  • Recurrences usually occur within 6/12
    • Depends on grade & depth
  • Risk factors for recurrence (Same as High risk factors)
    • Patient factors:
      • Immunosuppression
      • Burns wound
      • Previous RTx
  • Tumour factors:
    • Size of SCC > 2cm
    • Depth of invasion >4mm
    • Degree of differentiation
    • Perineural / vascular involvement
    • Location on head/neck

Graph View

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