Case 8- Acne and skin cancer Flashcards
Who does acne effect
Mainly young people between 12-24. Acne is more common in puberty as there is an increase in androgens
What does acne consist of
It is made from a mixture of non-inflamed and inflamed lesions. Non-inflamed lesions are comedones and can be open (blackheads) or closed (whiteheads). Inflamed lesions are called papules and postules.
Process of acne development
- Androgens increase sebum production in enlarged sebaceous glands.
- Follicles become impacted and distended by altered keratinocytes and sebum (comedones- blackheads, whiteheads)
- Proliferation of bacteria within the sebum (Propionibacterium acnes)
- Inflammation of the pilosebaceous unit.
- Inflammatory lesion (pustules, papules)
Biopsychosocial effects of acne
Acne can be very severe and cover extensive areas of the body including the face, chest and back. The lesions themselves can cause distress as well as long term skin changes resulting from then such as scarring and post-inflammatory hyperpigmentation. It can have psychological impacts such as: depression, anxiety, suicide, low self-esteem and reduced attachment to friends.
Basic advice given to patients on how to manage their acne
- Avoid over cleaning the skin as this can cause dryness and irritation, acne is not caused by poor hygiene
- Avoiding wearing make-up if possible, and if make-up is to be worn to try to use non-comedogenic preparations
- Avoiding picking and/or squeezing spots - can lead to scarring
- Maintaining a healthy diet
Principle of step wise approach to acne treatment
At each stage the treatment is given 8-12 weeks to work before moving on. Treatment may irritate the skin initially. If treatment is working continue for at least 12 weeks
Acne- single topical treatment
First treatment given. Can be a topical retinoid i.e. adapalene, Benzoyl peroxide. A topical antibiotic can also be given i.e. clindamycin, it will need to be given with benzoyl peroxide to prevent resistance.
Acne- Topical retinoid’s mechanism of action
Reduces comedones, is anti-inflammatory
Acne- oral antibiotics
Antibiotics such as lyme cycline or doxycycline, given for a maximum of 3 months. Needs to be given with benzoyl peroxide to prevent resistance. The combined oral contraceptive can be given to women as an alternative to antibiotics. You continue from 3 months after acne is controlled but then you stop it due to risks i.e. blood clot.
Benzoyl peroxide mechanism of action
1) Reduces comedones
2) Reduces sebum production
3) Inhibits growth of P.acnes bacteria
Mechanism of action of topical/ oral antibiotics
1) Anti-inflammatory
2) Anti-infective
Mechanism of action of combined oral contraceptive pill
Anti-androgen
Mechanism of action- Isotretinoin
Reduces sebum secretion
The third stage in acne treatment
• Refer to dermatology if they haven’t responded to two courses of antibiotics, it is severe acne associated with visible scarring, it is causing significant psychological distress and there is diagnostic uncertainty (unsure if its acne).
Specialist acne treatment
Once referred to dermatology, they will consider treatment with oral isotretinoin (a retinoid)
Contraindications of topical and oral retinoids
Topical and oral retinoids (adapalene, isotretinoin) are teratogenic so are contraindicated in pregnancy.
Contraindications of Tetracycline antibiotics
Tetracycline antibiotics (lymecycline, doxycycline) are also teratogenic and contraindicated in pregnancy.
Side effects of isotretanoin
As well as being teratogenic, isotretanoin has the potential for severe side effects and therefore can only be prescribed in hospitals under consultant supervision. Other side effects include dry skin, skin thinning, depression and mood swings. Don’t use when pregnant
The psychological impact of skin cancer
Surgical removal of skin cancer can be disfiguring especially on the face
Most common skin cancer order
1) Basal cell carcinoma- 75%
2) Squamous cell carcinoma
Why do most cancers occur in the epidermis?
They are exposed to UV
What gives rise to squamous cell carcinoma?
Keratinocytes give rise to Actinic Keratosis which is a precursor to squamous cell carcinoma.
What’s the most deadly skin cancer
Melanoma, derived from melanocyes
Role of melanin
Normally melanin gets packages in Melanosomes which get deposited into the keratinocytes and basal cells. The melanin covers the nucleus of the cell protecting it from UV radiation, which could cause mutations and cancer.
NMSC (non-melanoma skin cancer)
Refers to basal cell carcinoma, Actinic Keratosis and squamous cell carcinoma. Accounts for 90% of diagnosed skin cancers
Skin cancer epidemiology
Skin cancer is the most commonly diagnosed cancer in the UK and worldwide. There are more cases in hotter countries where the population have lower amounts of melanin i.e. Australia and USA.
Skin cancer and UV
95% of skin cancers are due to exposure to UV light and sunlight. The UV directly damages the DNA causing a thymidine dimer. In a thymidine dimer the T nucleotides join to each other forming kinks in the structure. The thymidine dimers cause DNA/DNA crosslinking. The UV can also indirectly damage DNA by damaging cells and creating free radicals which mediate oxidative DNA damage. This all leads to the activation of oncogenes and the inactivation of tumour suppressor genes. Leading to unregulated cell growth
How UVA damages DNA
Causes ageing and wrinkling, it is the longest wavelength and damages all layers of the skin (surface, epidermis and dermis)
How UVB damages DNA
Causes burning, it is medium wavelength and penetrates the skin surface and epidermis.
How UVC damages DNA
It rarely damages the skin, it is the shortest wavelength and is blocked by the ozone and lower atmosphere
Most common mutation in melanoma cell
A mutation in the BRAF oncogenes
Do you get skin cancer from a single period of UV exposure?
Damage from UV exposure is cumulative and increases your skin cancer risk over time. While your body can repair some of the DNA damage in skin cells, it can’t repair all of it. The unrepaired damage builds up over time and triggers mutations that cause skin cells to multiply rapidly. That can lead to malignant tumours.
What does Actinic keratosis look like?
Rough scaly lesions. As the most prominent risk factor is chronic skin exposure they are found on places exposed to the sun. This could be the face, lips, ears, arms, neck and scalp. Common in older patients
Actinic keratosis treatment
99% of individuals can be cured using Imiquimod. It stimulates the immune system to become activated and remove the cancer cells. It is a topical skin ointment. The appearance of the lesions will appear worse as the skin becomes necrotic and scabs over, eventually it will return to healthy skin.
Actinic keratosis when left untreated
When left untreated only 0.5% per year progress to squamous cell carcinoma
Risk factors for squamous cell carcinoma
Long term sun exposure and being immune-compromised
Squamous cell carcinoma pathology
Leads to scaly outgrowths with an open sores, they can be elevated growths with a central depression. Can look like a wart. They are vascularised so can often bleed and become crusty.
Squamous cell carcinoma treatment
98% of patients are cured with surgical incision, they remove the tumour and then sew the round up.
Squamous cell carcinoma when left untreated
When left untreated about 0.5% a year become invasive and spread, eventually through the lymphatic and blood system. To these patients chemotherapy is offered, there is a 15% 5 year survival prognosis which is poor.
Basal cell carcinoma risk factors
Intermittent sun exposure
Types of basal cell carcinoma (BCC)
There are 7 different types of basal cell carcinoma’s. There are 3 major types- Nodular BCC, Superficial BCC and infiltrative BCC.
Nodular BCC
The most common type, there is a single nodular growth which is either pink or flesh coloured. It has a pearly appearance and is slightly translucent. It may have overlying blood vessels, they can rupture leading to blooding and scabbing. Caused by the basal layer hyperproliferating. Forms a contained mass which doesn’t invade downwards into the skin. Good prognosis, removed through surgery (99%).
Basal cell carcinoma
Can be locally destructive and cause disfigurement
Superficial BCC
It grows out, like a puddle and does not grow downwards into the skin. Is a red, scabby plaque which is either pink or inflamed. Misdiagnosed as eczema or psoriasis. Not itchy unlike eczema. As it grows horizontally it has a really good prognosis through surgery (99%).
Infiltrative BCC
The most severe and aggressive type. They spread over a large area. Hard to remove because they cant tell where the tumour starts and ends. Looks like a scar or tissue injury so is often under-reported. They are transparent with a depression and rolled border. They grow downwards and into the skin. They send out finger-like projections.
Treatment for infiltrative BCC
Require specialised surgical excision known as ‘Mo’s surgery,’ where both the pathology and surgical team to work out where the tumour is. They cut around the clear margin to make sure they remove all the tumour. This technique is 95-99% effective.
Treatment for infiltrative BCC- true invasion
True invasion is extremely rare at less then 0.5%. They may not want surgery for infiltrative BBC on the face as it will lead to disfigurement. So, they may take a ‘Sonic Hedgehog’ inhibitor to slow the growth of the tumour and the activation of the smoothened receptor. It can be taken as a pill or a topical ointment. They can also remove some of the tumour and then take it.
What is melanin derived from?
Neural crest cells
Moles
Moles occur when melanocytes group together. Melanomas arise 50% from existing moles and 50% from normal skin.
How do melanocytes move
Through EMT (Epithelial mesenchymal transition)
Risk factors for melanoma’s
Fair skin (low melanin levels), many/atypical moles (increased concentration of Melanocytes) and family history (mutations on CDKN2A- p16 tumour suppressor gene).
Mutations in melanomas
1) Mutations on CDKN2A- p16 tumour suppressor gene
2) 50% of the metastatic melanoma’s caused have the B-RAF gene mutation.
3) Mutations in the mitogen-activated protein kinase (MAPK) pathway which is used in cancer cell growth, differentiation and survival.
Skin cancer- BRAF and MEK mutations
The mutations in B-RAF and MEK in this cycle leads to uncontrolled proliferation, survival, invasion and metastasis. Clinicians target this pathway to treat advanced melanomas.
Identifying melanoma’s
- Asymmetry- will look like its grown at an uneven rate, a normal healthy mole is round.
- Border- melanoma’s have a ragged or blurred border or edges.
- Colour- A mole has uniform colour whilst melanoma’s are uneven in their colour.
- Diameter- melanomas are often larger than 6mm
- Evolution- a melanoma may physically change and get bigger and more raised. Other new symptom such as inflammation, swelling, bleeding, itching or crusting are also indicative of melanoma progression
What score in the 7 point check list suggests skin cancer
All suspicious pigmented skin lesions scoring 3 points or more should be referred urgently
7 point check list- major features
Major feature of the lesion (2 points each)
• Change in shape
• Irregular shape
• Irregular colour
7 point check list- minor features
Minor feature of the lesion (1 point each) • Largest diameter of 7mm or more • Inflammation • Oozing • Change in sensation
Melanoma- when else should a referral be made
A referral should be considered for a pigmented or non-pigmented skin lesion if it is suggestive of nodular melanoma, and is more likely to spread (endophytic)
Superficial spreading melanoma
Most common type of melanoma, primarily grows horizontally like a ‘puddle’. It can invade and spread. Risk factor is intermittent sun exposure
Nodula melanoma
Primarily grows vertically, it is a burrowing mole which frequently invades and spreads. Most likely to cause invasion and metastasis
Nail melanoma
Within the nail. It grows both horizontally and vertically, appears brown. It is frequently ignored by patients and invades and spreads.
Amelanotic melanoma
Grows mainly vertically, frequently ignored by patients. Often invades and spreads
Dysplastic melanocyte nevus
Benign mole / melanocyte growth
Seborrheic keratosis
Waxy, scaly, slightly elevated appearance. The cause is not fully known. Not thought to be sun induced
Solar lentigo
Harmless patch of darkened skin due to excessive melanin
Dermatofibroma
Benign fibrous nodule. Reaction to insect bites etc
Treatment for non-invasive melanoma
Can be removed by surgical excision which has an excellent 98% curative prognosis. They would perform a football incision, cutting around the melanoma and the safe margin, which is skin that does not contain melanoma.
Invasive melanoma treatment and prognosis
Invasive melanoma is when the melanocytes have gone through the basement membrane and spread throughout the body. This has a 18% 5 year survival. Patients are offered radiotherapy and then chemotherapy. You do not die from the original tumour but from when it spreads through your body as melanocytes are mobile cells
Pharmacological treatment for NMSC
Fluorouracil (5fu) and Iminoquinone or SHH inhibitor (VISMODEGIB in BCC)
Pharmacological treatment for malignant melanoma
B-raf inhibitor or PD-1 inhibitor
What happens with the B-raf mutation in melanoma’s
It has a V600E mutation which keeps B-raf’s active site exposed so the cell continually goes through the cell cycle without its DNA being checked.
How does B-raf normally work
Normally growth factors induce a confirmational change in B-raf exposing it active site. The active site can bind to ATP, the ATP then phosphorylates a series of transcription factors which are responsible for the transcription and translation of G1 checkpoint proteins. The cell can then undergo DNA replication and enter the cell cycle.
Zelboraf
The drug Zelboraf binds to B-raf and prevents it from being turned on, preventing hyperproliferation. You give it to the patient after they have had the V600E mutation. After 6-9 moths this treatment no longer works as it undergoes molecular compensation. Instead of using B-raf it uses the sister enzyme C-raf. This is acquired resistance.
Molecular compensatory resistance to B-raf inhibitors
1) B-raf mutations make the cell divide inappropriately as it bypasses the g1-s checkpont
2) B-raf inhibitor blocks this action
3) But B-raf is a scaffold for C-raf
4) B-raf recruits and scaffolds C-raf and drives the cell progression through G1-S
5) The tumour comes back because the inhibitor does not effect C-raf, lots of B-raf is expressed to scaffold C-raf
