Squamous cell carcinoma (SCC) is a cancer of the skin involving keratinocytes. It is the second most common type of skin cancer (after basal cell carcinoma). It has a good prognosis and yields a good 5-year survival rate if detected early (99%).
It most commonly occurs in skin exposed to UV light and as such is most common in countries near the equator.
🦴 Anatomy
There are 3 layers of the skin - the epidermis, the dermis and the hypodermis.
Let’s look at these 3 layers in more detail:
- Epidermis
- Stratum corneum - as the name implies, this is the layer in which cornification is most prominent. The cells here have lost their nucleus and all other organelles and are highly keratinised. They are known as corneocytes - the terminally differentiated epidermal cell. The corneum layer is made up of 10-30 corneocytes stacked on top of each other. Th
- Stratum lucidum - this is the “clear layer”. It is a thin, clear layer of cells containing eleidin. Eleidin is a clear intracellular protein that tightens the connection between cells and improves the protection of the skin.
- Stratum granulosoum - this layer consists of 3-5 layers of flattened cell layers that produce keratohyaline granules which gives it a granular appearance. These granules are used for cross-linking of keratin filaments. They also secrete lipids and other waterproofing molecules.
- Stratum spinosum - these keratinocytes are held together by desmosomes. The stratum spinosum also contains Langerhans cells which are tissue-specific macrophages that help with immune function.
- Stratum basale - this is the deepest epidermal layer. It has dividing and non-dividing keratinocytes that are attached to the basement membrane by hemidesmosomes. Here the cells are dividing rapidly and the daughter cells migrate upwards. Melanocytes are present here and they are responsible for melanin production. Langerhans cells are also found here and they are sensory mechanoreceptors that are sensitive to touch.
“Epi“ means above. As such the name denotes that the epidermis lies above the dermis. It is the most superficial layer of skin and is made up of layers of keratinocytes that have undergone differing levels of maturation. With each level of maturation there is increased keratinisation and migration towards the surface. This process is known as cornification (the process in which skin, as well as nails and hair, become dry and hard). There are 5 distinct layers of the epidermis:
- Dermis
- Blood vessels
- Cutaneous nerves
- Fibroblasts - these produce the extracellular matrix, predominantly made up of collagen and elastin.
- Mast cells - these are innate immune cells containing histamine granules.
- Skin appendages - this includes hair follicles, sebaceous glands, sweat glands, nails. These structures actually derive from the epidermis and descend into the epidermis during development.
- The pilosebaceous unit refers to the hair follicle, the hair shaft, and the sebaceous gland. The sebaceous gland releases sebum through the process of holocrine secretion (the contents are produced in the cytoplasm of the cell and released into the gland through rupture of the plasma membrane). Sebum contains lipids and fatty acids that lock in moisture and make the skin soft. However, it also may predispose the skin to acne in some instances. The hair follicle has an associated arrector pili muscle which contracts to pull the hair follicle upright. It is involved in thermoregulation and emotional response. It also puts pressure on the sebaceous gland which aids in directing sebum to the hair shaft.
- Sweat glands present in the dermis are both eccrine and apocrine sweat glands. Eccrine sweat glands are involved in thermoregulation and they release a clear, odourless substance to help cool the skin. Apocrine sweat glands are larger. They are located in the axillary and genital regions. It’s contents may be broken down by microbes on the skin which is what produces body odour.
- Hypodermis
The dermis has 2 layers which are not as clearly defined. These are the papillary layer (superficial) and the reticular layer (deep). The reticular layer is thicker and has bundles of collagen fibres that provide rigidity and durability.
There are numerous structures present in the dermis:
The hypodermis is another name for the subcutaneous tissue that lies deep to the dermis. It functions to store adipose tissue.
Pathophysiology
Malignant transformation in keratinocytes within the epidermis occurs primarily due to cumulative ultraviolet (UV) radiation exposure. UV radiation results in DNA damage and particularly causes mutations that inactivate tumour suppressor genes and activate proto-oncogenes. It is primarily UV-B radiation which has a wavelength of 290-320nm (while UV-A has a wavelength of 320-400nm). This higher energy allows it to penetrate the outer layers of the epidermis and cause more DNA damage. Radiation, burns, UV-A light, arsenic, tar, human papillomavirus and, interestingly enough, red tattoo ink are all associated with risk of SCC transformation.
⚠️ Risk factors
🔢 😷 Classification and presentation
We will take a look at varying stages of SCCs ranging from pre-cancerous and early stages, to invasive and finally metastatic SCC. We shall also discuss how this may present in each case:
Actinic keratosis (AK), also known as solar kearotisis, is considered to be a pre-cancerous scaly skin lesion that occurs due to chronic UV exposure.
😷 Presentation
- Rough, scaly plaques on areas that are sun-exposed (especially on the face and head).
- They may be pink, red, brown or the same tone as the skin complexion.
- It may be present on the lower lip and this is known as actinic cheilitis.
- It may appear as a growth of keratin (that is benign) known as a cutaneous horn.
🔍 Investigations
- Biopsy - atypical keratinocytes in the basal and squamous layers.
🧰 Management
As it does pose a risk of progression, we want to prevent further risk through:
- Sun cream and sun avoidance
- Fluorouracil cream - prevents DNA synthesis. It may be given in a 2-3 week course. It may induce inflammation of the skin and as such hydrocortisone cream may be given to manage the inflammation.
- Diclofenac cream - it is not fully understood how diclofenac works in actinic keratosis but seeing as AK is shown to increase prostaglandin synthesis in the affected skin, it has some efficacy.
- Imiquimoid cream - induces an immune response that produces apoptosis of the affected tissue.
- Crytotherapy
- Curettage and cautery
Bowen’s disease is a type of squamous cell carcinoma in-situ. It is a precancerous disease of the integumentary system that also occurs due to UV exposure but also may be due to high-risk HPV (HPV 16 & 18). Chronic arsenic exposure in water has also shown to be associated with Bowen’s disease.
😷 Presentation
- Irregularly shaped or well defined, scaly, red patches - the patches are about 10-15mm size commonly. They are seen on sun-exposed areas such as the head and neck and legs.
- Erythroplasia of Queyrat - this is a form of Bowen’s disease that occurs on the glans penis.
🔍 Investigations
💡 It is difficult to differentiate Bowen’s disease from SCC and as such a skin biopsy is essential.
- Biopsy - atypical keratinocytes confined to the epidermis.
🧰 Management
- Sun cream and sun avoidance
- Fluorouracil cream - prevents DNA synthesis. It may be given in a 2-3 week course. It may induce inflammation of the skin and as such hydrocortisone cream may be given to manage the inflammation.
- Diclofenac cream - it is not fully understood how diclofenac works in actinic keratosis but seeing as AK is shown to increase prostaglandin synthesis in the affected skin, it has some efficacy.
- Imiquimoid cream - induces an immune response that produces apoptosis of the affected tissue.
- Crytotherapy
- Curettage and cautery
This is the cancerous form of SCC that invades into the deeper layers of the skin.
😷 Presentation
- Lesin on sun-exposed sites - this is commonly the head and neck. The dorsum of the hands and arms is another common site.
- May have a cauliflower-like appearance.
- Rapidly expanding
- Central ulceration may be present.
- Friable and bleeds easily
- Painless
🔍 Investigations
- Biopsy - this may be a full thickness excisional biopsy or may be a punch biopsy. An excisional biopsy is preferred as it facilitates diagnosis and treatment simultaneously. However, a punch biopsy might be preferred if the lesion is large and unable to be excised at the time.
- ≥2cm in diameter
- Located on ear, face, hands, feet, or genitalia
- Elderly or immunosuppressed
- Histological features - thicker than 2mm, poorly differentiated, blood or nerve involvement, subcutaneous invasion.
With the excisional biopsy a 4mm peripheral margin is needed. For higher risk lesions, a 6mm peripheral margin is needed.
Higher risk lesions include:
⚖️ Prognosis
Good prognosis | Poor prognosis |
Well-differentiated tumour | Poorly differentiated tumour |
<20mm diameter | >20mm diameter |
<2mm deep | >4mm deep |
No associated disease | Immunosuppressed |
🧰 Management
- 🏆 Surgical excision with 4mm peripheral margin - for higher risk lesions this increases to a 6mm peripheral margin.
💡 For high-risk patients and cosmetically important sites we may use Mohs micrographic surgery. This is a type of procedure in which the surgeon acts as the pathologist as well as doing reconstructive work. The cancerous tissue is removed, analysed at an on-site lab (which allows the surgeon to determine if and where any cancerous cells remain), and then the wound is repaired. It spares healthy tissue while remaining cosmetica appeal.
If surgery is not feasible or if multiple lesions are present we can also consider:
- Intralesional injections of chemotherapeutic agents
- Systemic retinoids
- Radiotherapy
3% of cutaneous SCCs become metastatic. This is more common in immunosuppressed individuals.
The most common sites include: lymph nodes (80%) as well as lungs, liver, bone and brain.
Keratoacanthoma is another well-differentiated squamoprolifertative keratotic lesion that is now considered a low-risk histological variant of SCC.
😷 Presentation
- Rapidly growing, firm dome-shaped nodule
- Central keratotic plug
The lesions may be solitary or multiple. They are typically 10-20mm in size but can grow to be much larger in weeks or months.
🔍 Investigations
- Biopsy - central hyperkeratotic crater surrounded by well-differentiated squamous epithelial cells
🧰 Management
It is managed in the same manner as an invasive SCC.
The lesions may spontaneously regress within 3 months which forms a scar.
A Marjolin ulcer is a rare formation of an SCC in a scar or ulcer. It most commonly occurs with thermal burn scars but may also form with osteomyelitic lesions, surgical scars, venous ulcers and pressure ulcers. It may take years after the initial injury for the Marjolin ulcer to develop (on average 30 years).
😷 Presentation
- Non-healing lesion with excessive granulation tissue and foul-smelling pus - the lesion is typically flat and hard with raised margins.
- Friable and bleeds easily
- Painful
🔍 Investigations
💡 A Marjolin ulcer should be suspected if an ulcer persists for ≥3 months at the site of a scar.
- Biopsy - well-differentiated SCC with evidence of chronic inflammation, necrosis and atypical keratinocytes.
🧰 Management
It is managed in the same manner as an invasive SCC.