non-melanoma

Non- melanoma is a slow developing cancer that affect the upper layers of the skin

Basal Cell Carcinoma is a superficial (located on the surface) cancer that is slow growing and arises from keratinocytes. Metastasis (development to different region) is rare but local growth is destructive. It is the most common type of skin cancer.

Squamous Cell Carcinoma is a malignant (harmful) tumour of cells- keratinocytes, that invades the tissue of the skin (dermis). This i9s the second most common type of skin cancer and can de developed from actinic keratoses.

Epidemiology

Squamous cell carcinoma
- Affects 1.8 million cases yearly in the United States [1]
- The incidence increases with increased age
- Rates of squamous cell carcinoma is higher in lighter- skinned people [2]
- According to NICE guidelines, approx 25,000 cases are diagnosed each year
- A full time GP is likely to diagnose at least 1 person every 1-2 years [3]
Basal cell carcinoma
- Particularly common in white populations and in the US, the incidence has increased by more than 10% per year
- The lifetime risk (risk of something occurring at some point in a lifetime) of basal cell carcinoma developing is 30% [4]
- According to NICE, approx 75,000 cases of basal cell carcinoma are diagnosed each year
- A full time GP is likely to diagnose at least one person with basal cell carcinoma per year. [3]

Source: DermNetNZ.org

Non-melanoma
Pigmented basal cell carcinoma seen with a dermoscopy (used to examine the skin)

Source: DermNetNZ.org

Non-melanoma
Dermoscopic image of actinic keratosis

Pathophysiology [5]
- Medical Student
  - Ultraviolet (UV) Radiation Exposure: UV radiation causes damage to the DNA in skin cells, leading to mutations that can promote the development of cancerous cells.
  - DNA Damage and Mutations: UV radiation induces direct damage to the DNA of skin cells. Specifically, it causes the formation of pyrimidine dimers. Failure to repair these UV-induced DNA lesions properly can result in genetic mutations that accumulate over time, increasing the risk of cancer development.
  - Loss of Cell Cycle Control: The mutations in critical genes, such as tumour suppressor genes and oncogenes, disrupt the normal cell cycle control mechanisms. This leads to uncontrolled cell proliferation and the accumulation of cancerous cells.
  - Inactivation of Tumour Suppressor Genes: Tumour suppressor genes, such as TP53 (p53) and PTCH1, play a vital role in preventing the growth of abnormal cells and promoting DNA repair. Mutations in these genes can result in their inactivation, enabling the uncontrolled growth of cancer cells.
  - Activation of Oncogenes: Oncogenes are genes that regulate cell growth and division. Mutations or other changes in these genes can lead to their activation, promoting cell growth and contributing to cancer development.
  - Inflammation: Chronic inflammation, often caused by prolonged exposure to UV radiation, can contribute to the development of non-melanoma skin cancer. Inflammatory mediators and cytokines can promote the growth of cancer cells and inhibit the immune system's ability to recognize and eliminate abnormal cells.
  - Immune System Evasion: Cancer cells can develop mechanisms to evade the immune system's surveillance and destruction, allowing them to grow and spread unchecked.
  - Angiogenesis: Non-melanoma skin cancers can induce the formation of new blood vessels (angiogenesis) to ensure a steady blood supply to support their growth and spread.
  - Invasion and Metastasis: As non-melanoma skin cancers progress, cancer cells can invade surrounding tissues, including deeper layers of the skin and underlying structures. In some cases, cancer cells may also enter the lymphatic system or bloodstream, leading to metastasis to distant organs, although this is relatively rare for non-melanoma skin cancers compared to melanoma.
- Patients
  - Ultraviolet (UV) Radiation Exposure: This exposure can be found when in contact with the sun or tanning beds. The UV radiation damages the DNS in skin cells which can increase the risk of changes to the DNA sequences. This can promote the development of cancerous cells.
  - DNA Damage and Mutations: UV radiation induces direct damage to the DNA of skin cells. Specifically, it causes abnormal links between DNA bases- these encode the biological information needed to make a protein. Failure to repair these can result in genetic mutations that accumulate over time, increasing the risk of cancer development.
  - Loss of Cell Cycle Control: The mutations in genes responsible for significant processes such such as tumour stopping and cancer development is disrupted in their normal cell cycle control mechanisms. This leads to uncontrolled cell growth and the accumulation of cancerous cells.
  - Loss of activity of Tumour Suppressor Genes: Mutations in genes can result in the inactivation of tumour suppressor genes (these prevent tumour formation), therefore, this enables the uncontrolled growth of cancer cells.
  - Activation of Oncogenes: Oncogenes are genes that manage cell growth and division. Mutations or other changes in these genes can lead to their activation, promoting cell growth and contributing to cancer development.
  - Inflammation: Long term inflammation, often caused by prolonged exposure to UV radiation, can contribute to the development of non-melanoma skin cancer. Substances and proteins involved in the inflammation process can promote the growth of cancer cells and stop the immune system's ability to recognise and remove abnormal cells.
  - Immune System Avoidance: Cancer cells can develop mechanisms to evade the immune system's recognition and destruction, allowing them to grow and spread unchecked.
  - Angiogenesis: Non-melanoma skin cancers can induce the formation of new blood vessels to ensure a steady blood supply to support their growth and spread.
  - Invasion and Metastasis: As non-melanoma skin cancers progress, cancer cells can invade surrounding tissues, including deeper layers of the skin and underlying structures. In some cases, cancer cells may also enter the lymphatic system (the network of lymph that circulated the body) or bloodstream, leading to the growth and development of the cancer into distant organs, although this is relatively rare for non-melanoma skin cancers compared to melanoma.

Causes [1]
- Overexposure to ultraviolet light from the skin/artificial tanning beds and sunlamps

Risk factors
- History of non-melanoma/ skin cancer
- Pale skin
- Large number of moles/freckles
- Suppressed immune system caused by medication
- Weakened immune system with co-existing medical conditions
- Older age
- Blue eyes or blonde/red hair
- Exposure to certain chemicals [6,7]

Source: Atlas of Black Skin

Non-melanoma
Raised white lesion seen in squamous cell carcinoma

Source: Atlas of Black Skin

Non-melanoma
Pigmented basal cell carcinoma

Presentations [8]
- Basal cell carcinoma
  - Open sores that bleed/ooze/crust
  - Redness
  - Raised patches
  - Crusting or itching of the affected skin
  - Pink/red/pearly-white bump
  - White/yellow/waxy areas
  - Poorly defined borders
- Squamous cell carcinoma
  - Wart-like growth
  - Scaly appearance of the skin
  - Irregular/poorly defined borders
  - Open sores
  - Raised growth
  - Rough surface with central dip (depression)

Investigations [6]
- Biopsy
  - A small procedure where a sample of all of the tumour is taken from the skin to be studied under the microscope
  - This usually takes several weeks before results are available
- Further tests such as lymph node examination may be required
  - Used to assess whether the cancer has spread
- Fine needle aspiration
  - In a case of concerns about cancer spreading, may be needed to do a biopsy on a lymph node

Source: DermNetNZ.org

Non-melanoma
Basal cell carcinoma affecting the face

Differential diagnosis [9]
- Psoriasis
- Seborrheic keratoses- non cancerous skin growth
- Sebaceous hyperplasia- growth of sebaceous glands (glands that grow near hair follicles)
- Nevus (mole)
- Cherry angioma- overgrowth of blood vessels that create cherry red bumps

Management [1]
- Medical students
  - In cancer care, different specialists work together in a multidisciplinary team, these include dermatologists, surgeons, plastic surgeons, radiation oncologists, and medical oncologists. Other healthcare professionals involved in the care team include physician assistants, nurse practitioners, nurses, social workers, pharmacists, counsellors, and dieticians.
  - Treatment options and recommendations:
    - Dependent on factors like tumour size, location, side effects, patient's preferences, and overall health.
    - Shared decision-making between patients and doctors to choose appropriate treatments.
      - Common treatments for non-melanoma skin cancer:
        Surgery:
        Removal of tumor and surrounding tissue
        Different procedures based on tumor type and size.
        Radiation Therapy:
        Use of high-energy rays to destroy cancer cells.
        Given externally or internally (brachytherapy).
        May be used instead of surgery or after surgery, especially for involved lymph nodes.
        Other Local Treatments:
        Photodynamic therapy
        Cryotherapy
        Laser therapy for precancerous skin conditions or top-layer cancer.
        Therapies using Medication:
        Medications may be given systemically or locally.
        Types include:
        Chemotherapy: Drugs applied topically for skin cancer treatment
        Targeted therapy: Drugs like vismodegib and sonidegib for advanced basal cell cancers
        Immunotherapy: Drugs like cemiplimab, pembrolizumab, avelumab, and retifanlimab for various non-melanoma skin cancers
- Patients
  - In cancer care, different specialists work together in a multidisciplinary team, these include dermatologists, surgeons, plastic surgeons, radiation oncologists (doctors who specialise in cancer using radiation therapy), and medical oncologists. Other healthcare professionals involved in the care team include physician assistants, nurse practitioners, nurses, social workers, pharmacists, counsellors, and dieticians.
  - Treatment options and recommendations:
    - Dependent on factors like tumour size, location, side effects, patient's preferences, and overall health.
    - Shared decision-making between patients and doctors to choose appropriate treatments.
      - Common treatments for non-melanoma skin cancer:
        Surgery:
        Removal of tumor and surrounding tissue
        Different procedures based on tumor type and size.
        Radiation Therapy:
        Use of high-energy rays to destroy cancer cells.
        Given externally (applied without touching the patient) or internally (inside the body)
        May be used instead of surgery or after surgery, especially for involved lymph nodes (areas holding lymph which filters foreign substances from the body).
        Other Local Treatments:
        Photodynamic therapy (using a drug to make cells sensitive to light paired with light exposure- destroying cancer cells)
        Cryotherapy (uses extreme coldness to destroy cancer cells)
        Laser therapy (use of lasers to destroy harmful cells) for precancerous skin conditions or top-layer cancer.
        Therapies using Medication:
        Medications may be given systemically (affecting the entire body) or locally (affects specific areas of the body)
        Types include:
        Chemotherapy (using chemicals to treat cancer): Drugs applied to the skin
        Targeted therapy (treatment that targets proteins that control how cancer cells grow and replicate): Drugs like vismodegib and sonidegib for advanced basal cell cancers
        Immunotherapy (uses substances to boost the immune response to destroy cancer cells): Drugs like cemiplimab, pembrolizumab, avelumab, and retifanlimab for various non-melanoma skin cancers.

Source: Waikato District Health Board; DermNetNZ

Non-melanoma
Squamous cell carcinoma on the cheek

Complications [10]
- Scarring after treatment
- Hyper/ hypo-pigmentation at sites of treatment
- Tightness and skin texture change due to radiation therapy
- Lymphedema- swelling of the lymphatic system, leads to fluid buildup
- Wound infection after surgery
- Hemeatoma- bleeding under the surface of the skin
- Numbness and pain of the sites of treatment
- Damage to the muscles/nerves/bones due to untreated cancer
- Metastasis- cancer can return and develop to another part od the body
- Mental health (anxiety and depression) caused by diagnosis and potentially due to treatment

Myths behind non-melanoma cancers [11]
- Darker skinned people don’t get skin cancer
- Only sun exposure can cause skin cancer
- Only older people get skin cancer
- High SPF sunscreen completely protects you from skin cancer
- Tanning beds don’t pose as a risk for skin cancer
- You don’t need to wear sunscreen in winter or cloudy days

Questions you may want to ask your doctor
- What is the process of investigating skin patches/areas of concern?
- Will removing the skin cancer be effective as a single form of treatment?
- How do I determine the stage of cancer?
- What can I do to prevent the skin cancer spreading?
- How can I manage any complications of my skin cancer?
- What follow-up support can I get during and after treatment?

Support
- Macmillan Cancer Support
- Cancer.net
- NHS Inform

Bibliography

[1] https://www.msdmanuals.com/en-gb/professional/dermatologic-disorders/cancers-of-the-skin/squamous-cell-carcinoma?query=squamous

[2]https://wiki.cancer.org.au/australia/Guidelines:Keratinocyte_carcinoma/Epidemiology_SCC

[3] https://cks.nice.org.uk/topics/skin-cancers-recognition-referral/background-information/prevalence/

[4] https://www.uptodate.com/contents/epidemiology-pathogenesis-clinical-features-and-diagnosis-of-basal-cell-carcinoma#H2

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307792/

[6] https://www.nhs.uk/conditions/non-melanoma-skin-cancer/

[7] https://www.nhsinform.scot/illnesses-and-conditions/cancer/cancer-types-in-adults/skin-cancer-non-melanoma#causes-of-non-melanoma-skin-cancer

[8] https://www.cancer.net/cancer-types/skin-cancer-non-melanoma/symptoms-and-signs

[9] https://sundoctors.com.au/blog/top-5-conditions-often-mistaken-skin-cancer/

[10] https://www.everydayhealth.com/skin-cancer/complications/

[11] https://www.mdanderson.org/publications/focused-on-health/10-skin-cancer-myths-debunked.h14-1592991.html

Actinic Keratosis

Actinic keratoses are precancerous (small chance of developing into cancer) patches of skin (that are likely to be exposed to the sun. eg. face, hands) that change due to frequent and long term exposure to the sun. This condition affects the skin cells- known as keratinocytes. It has a chance of progression into squamous cell carcinoma but ranges from less than 1 to 10% in likelihood of progression.

Epidemiology

People with fair skin are most likely to develop actinic keratoses according to studies conducted in Australia, Northern Europe and the US [1]
NICE estimates that over 23% of the population in the UK aged 60 and above have actinic keratosis [2]
The WHO have estimated that the highest levels are observed in Caucasians living close to the Equator [3]
A study, carried out in Austria, found a prevalence of actinic keratoses of 31% of patients over 30 years old.
The prevalence was also higher in men than in women and increased with age [4]

Pathophysiology [5]
- See above pathophysiology

Causes [6]
- Damage to the skin caused by UV (ultraviolet light) from exposure to:
  - Tanning beds
  - The sun

Risk factors [7]
- Exposure of UV rays from the sun or tanning beds
- People with pale skin
- People with blonde/red hair
- People with blue/green/grey eyes
- Increased age
- Weakened immune systems (eg. AIDS, organ transplant etc)
- Rare conditions that cause hypersensitivity to UV rays (eg. albinism- no melanin, xeroderma pigmentosum- condition causing increased reactions/sensitivity to the sun)

Presentations [6]
- Scaly patches found on areas of the skin
- Some can form a horn shaped growth
- Thickened skin
- Pigmentation change to pink, red, grey or brown
- Roughness
- Raised spots
- Dryness

Investigations [8]
- Clinical assessment based on presenting symptoms and appearance of patches
- Dermoscopy is an exam of the skin using skin surface microscopes to assess the areas of concern
- Biopsy (a sample of the skin is taken) is necessary to exclude differential diagnosis such as squamous cell carcinoma

Differential diagnosis [9]
- Seborrheic keratosis (dandruff)
- Squamous cell carcinoma- type of skin cancer that affects the sqaumous cells
- Bowen’s disease- an early form of squamous cell carcinoma
- Solar lentigo- harmless patch of darkened skin
- Stucco keratosis- multiple harmless wart like lesions (sores) typically small with a stuck on appearance
- Basal cell carcinoma- type of skin cancer that affects the basal cells
- Porokeratosis- abnormal keratinisation (process where skin cells form and produce keratin) with ridge-like borders on the skin
- Clear cell acanthoma- a rare, non-cancerous skin tumour
- Psoriasis- skin condition that causes dry, flaky patches of skin
- Lupus erythematosus- disease where the immune system attacks the body’s tissues, causing inflammation and damage to the skin
- Lichen planus- a condition that is non-infectious and causes an itchy rash that affects many areas of the body
- Viral warts- a common, non-cancerous condition that causes regions of damage through infection

Management [12]
- Topical therapies
  - 3% Diclofenac
  - 5% Fluorouracil (5-FU)
  - 5% Imiquimod
  - 0.5% 5-FU+10% Salicylic acid
  - 3.75% Imiquimod
- Other therapies
  - Liquid Nitrogen
  - Curettage

Complications [8]
- Risk of developing into squamous cell carcinoma
- Cutaneous horn (bone structure with keratin) formation
- Actinic cheilitis- lip involvement with actinic keratosis
- Basal cell carcinoma- type of skin cancer that affects the basal cells
- Melanoma- a cancerous skin condition that affects the melanocytes
- Rare forms of skin cancer such as Merkel cell carcinoma

Myths behind actinic keratoses
- Actinic keratoses always turns into squamous cell carcinoma
- Actinic keratoses does not require treatment
- Actinic keratoses is cancerous [10,11]

Questions you may want to ask your doctor
- How can I tell if my patches change/ develop?
- How can I prevent actinic keratoses developing in everyday activities?
- How long does treatment take to be effective?
- What is the process of investigating actinic keratoses?
- What happens if I don’t treat actinic keratosis?