Basal cell carcinoma

Basal cell carcinoma is the most common type of skin cancer. It affects the basal cells located in the stratum basale of the epidermis. It is a non-melanoma skin cancer. Similar to the other skin cancers its incidence is very much related to ultraviolet (UV) exposure, particularly UV-B exposure.

🦴 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

“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:

1. 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
2. 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.
3. 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.
4. 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.
5. Stratum basale - this is the deepest epidermal layer. It has dividing (basal cells) and non-dividing keratinocytes (post-mitotic 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.

• Dermis

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:

1. Blood vessels
2. Cutaneous nerves
3. Fibroblasts - these produce the extracellular matrix, predominantly made up of collagen and elastin.
4. Mast cells - these are innate immune cells containing histamine granules.
5. 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.
6. 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.
7. 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 hypodermis is another name for the subcutaneous tissue that lies deep to the dermis. It functions to store adipose tissue.

Pathophysiology

The mechanism by which BCCs form involves both environmental factors and genetic factors:

• Environmental factors - the most important factor is chronic UV exposure. UV-B has a wavelength of 290-320nm. This wavelength has higher energy and allows the photons to penetrate the epidermis and damage the basal cells. DNA also absorbs UV-B radiation more readily. This induces DNA damage and molecular changes.
• Genetic factors - this DNA damage induces mutations in tumour suppressor gene PTCH1/PTCH2 and SMO and SUFU. These are all involved in the Hedgehog signalling pathway. Aberrant activation of this pathway is what leads to BCC formation.

Let’s discuss the hedgehog signalling pathway in more detail…

Hedgehog signalling pathway:

The Hedgehog signalling pathway is involved in cell growth and differentiation during embryonic development. In adulthood, the pathway remains active but at a much lower level. It again functions to regulate differentiation and cell growth. Abnormal activation is what can lead to the development of various cancers with BCC being one of the main ones.

Before we discuss its involvement in BCC pathogenesis, let’s discuss some of the components of this pathway:

1. PTCH1 and PTCH2 (patched proteins) - these are the receptors for the Hedgehog ligands. PTCH1 normally inhibits Smoothened protein which prevents downstream activation of the pathway.
2. Hedgehog ligands - this is the ligand that binds to PTCH1 and PTCH2 it prevents the inhibition of Smoothened protein - allowing it to become active.
3. Smoothened protein (Smo) - when activated, the Smo, activates transcription factors which enter the nucleus and promote the expression of target genes for cell proliferation and survival. When Smo is activated, SUFU is inhibited.
4. Suppressor of fused (SUFU) - SUFU downregulates Hh pathway by binding to the transcription factors and preventing their activation

In BCC, mutations of these genes (most commonly PTCH1 gene) result in activation of SMO in the absence of Hedghehod ligands. This means the pathway is uncontrollably activated. This results in proliferation and survival of basal cells in the epidermis. Excessive cell division and resistance to apoptosis is what ultimately leads to development of BCC.

⚠️ Risk factors

• UV radiation - especially UV-B and especially in the following patient groups:
• Lighter skin tones (Fitzpatrick I and II)
• History of sunburns
• History of BCC
• Naevus (mole) present on extremity
• Autoimmune conditions
• Immunocompromised
• Age >40 years
• Male sex
• Exposure to the following:
• Arsenic
• Ionising radiation
• Phototherapy
• Albinism
• Xeroderma pigmentosum - an autosomal recessive disorder characterised by extreme UV radiation sensitivity.
• Basal cell naevus syndrome (also known as Gorlin syndrome) - a syndrome characterised by multiple early onset basal cell carcinomas, odontogenic keratocysts and other tumours.

🔢 Classification

There are multiple subtypes of BCC:

1. Nodular BCC - this is the most common form of BCC (60%). It presents as a raised translucent/pearly white papule with telangiectasia on the surface.
2. Superficial BCC - this is the second most common form of BCC. It presents as a thin, scaly plaque (a superficial erythematous macule) that resembles eczema. It is usually on the upper trunk and shoulders. They are often >20mm at presentation. They are particularly responsive to medical as opposed to surgical treatment.
3. Micronodular BCC - presents as a cluster of small nodules (only seen on histology). It can be flesh-coloured or slightly erythematous. It is more likely to invade deeper and has poorly defined borders.
4. Metatypical BCC (basosquamous carcinoma) - this subtype shows features of both BCC and squamous cell carcinoma. They are more aggressive and have a higher potential for metastasis as compared to other BCC subtypes.
5. Morpheaform BCC - appears a waxy, scar-like lesion with ill-defined borders. It may be slightly depressed and whitish. It is the most infiltrative subtype. It is often found in mid-facial sites.
6. Infundibulocystic BCC - multiple small cystic nodules with a central pore. It may resemble the infundibula of a hair follicle on histology.
7. Mixed BCC - may have features of more than one subtype within the same tumour.
8. Periocular BCC - occurs around the eye, typically as a nodular or morpheaform lesion. It may be difficult to treat based on its location.

😷 Presentation

• As nodular is the most common subtype of BCC, it typically presents as a non-healing, well-defined, pearly white papule with telangiectasia. It may also have a central umbilication or rolled edge (raised lip around the periphery).
• They are typically located on areas with sun exposure (face and neck).
• Lesions are typically painless
• Lesions may be itchy and may bleed.

🔍 Investigations

BCC can only be diagnosed histologically, as such a biopsy must be performed.

This may be done in 3 ways:

1. Punch biopsy - best for cosmetically non-challenging areas. It is only possible with small lesions.
2. Shave biopsy - this is reserved for cosmetically challenging areas, such as the face. A blade is used to shave off the top layer of the skin to obtain the sample.
3. Excisional biopsy - this means the biopsy is done after removing the lesion surgically. It is both diagnostic and therapeutic.

Referral guidelines:

Urgent referral is not routinely required for BCC.

NICE suggests the following:

• Consider routine referral for people if they have a skin lesion that raises the suspicion of BCC.
• Only consider a suspected cancer pathway referral for people with a skin lesion that raises the suspicion of a basal cell carcinoma if there is a particular concern that a delay may have significant impact (because of factors such as a lesion site or size).

🧰 Management