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Anatomy of the Skin

• The skin consists of three layers: epidermis, dermis, and subcutaneous tissue.

Epidermis

• The epidermis contains:
  • Keratinocytes: The primary cell type.
  • Langerhans cells.
  • Merkel cells: Associated with sensory neurons.
  • Melanocytes: Produce melanin.
• Layers of the epidermis include:
  • Stratum corneum.
  • Stratum lucidum.
  • Stratum granulosum.
  • Stratum spinosum.
  • Stratum basale.

Dermis

• The dermis is composed of:
  • Papillary dermis.
  • Reticular dermis.

Subcutaneous Tissue

• Lies beneath the dermis.

Skin Cancer Facts

• In Australia:
  • Over 2000 people are treated for skin cancer per day, totaling around 750,000 per year.
  • 2 in 3 Australians will be diagnosed with skin cancer by age 70.
  • Skin cancer is the most common cancer, accounting for about 80% of newly diagnosed cancers each year.
  • More than 12,500 melanoma cases are diagnosed annually.
  • Around 2,000 deaths per year are attributed to melanoma.
  • Melanoma is more common in men, who are 2.5 times more likely to die from it.
  • Melanoma is the 6th most common cause of cancer death in Australian men and 10th in Australian women.
  • Prevention: Slip, Slop, Slap, Seek, and Slide; get new or changing spots checked.

Skin Cancer Risk Factors

• Anyone can develop skin cancer, but risk factors include:
  • UV exposure from tanning beds or the sun.
  • Past sunburns, especially severe, blistering ones.
  • Fair complexion: Blond or red hair, light-colored eyes, and freckles.
  • Weakened immune system: Organ transplant recipients or those with autoimmune diseases.
  • Family history: Increased risk if a sibling or parent had skin cancer.

UV Penetration into the Skin

• UVA: 320-400 nm.
• UVB: 290-320 nm.
• UVC: 200-290 nm.
• UV radiation affects keratinocytes, melanocytes, and fibroblasts.

UV and Skin Cancer

• UV radiation is associated with:
  • Approximately 65% of melanoma cases.
  • Approximately 90% of non-melanoma skin cancers, including Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC).

UV-Induced Skin Carcinogenesis

• Process involves:
  • DNA damage (CPD and 6-4PP).
  • Stalled replication forks.
  • Release of Damage-Associated Molecular Patterns (DAMPs).
  • Activation of NRF2 and antioxidant defenses.
  • DNA repair mechanisms (XPC, p53).
  • Metabolic alterations leading to malignant transformation.
  • Activation of transcription factors (AP-1, NF-kB, IRF3).
  • Cell proliferation and survival via ERK and PI3K pathways.
  • Increase in mutation burden.
  • Inflammation and immunosuppression due to inflammatory cytokines and PD-L1 upregulation.

Types of Skin Cancer

• Main types include:
  • Basal Cell Carcinoma (BCC).
  • Squamous Cell Carcinoma (SCC).
  • Melanoma.
  • Merkel Cell Carcinoma (MCC).
  • Others: Dermatofibrosarcoma protuberans (DFSP), Kaposi’s sarcoma, Microcystic adnexal carcinoma (MAC), Sebaceous carcinoma, Undifferentiated pleomorphic sarcoma, Extramammary Paget’s disease (EMPD).

Basal Cell Carcinoma (BCC)

• Originates from stratum basale.
• The most common type of skin cancer, making up ~75% of cases.
• Grows slowly and appears as shiny, waxy bumps or nodules.
• Commonly found on areas with high sun exposure (head, arms, legs, face).
• Rarely spreads beyond the original tumor site.
• In rare, aggressive cases, BCC can spread to other parts of the body.

Squamous Cell Carcinoma (SCC)

• Originates from keratinocytes in the stratum spinosum.
• ~20% of skin cancer cases.
• More aggressive than BCC but easily treated when found early.
• Appears as a red, scaly bump or nodule, commonly on the face.
• Can spread to other parts of the body, especially in fair-skinned individuals.
• Most SCCs are successfully treated.
• Can arise inside the body in places like the mouth, throat, or lungs.

Melanoma

• Originates from melanocytes.
• ~2% of skin cancer cases.
• Accounts for more than 75% of all deaths caused by skin cancer.
• Commonly starts as a mole that becomes cancerous, appearing as a large brown spot with irregular borders.
• Most commonly found on the head, neck, or trunk.
• Malignant melanoma is a serious form of skin cancer.
• Curable when detected and treated early; becomes more difficult to treat and can be deadly if it spreads.

Merkel Cell Carcinoma (MCC)

• A rare, aggressive form of skin cancer with a high risk of recurrence and metastasis.
• 40 times more rare than melanoma.
• Named after Merkel cells due to similar microscopic features.
• Recent research suggests it may not originate directly from normal Merkel cells.
• Appears as a pearly pimple-like lump; grows rapidly.
• More deadly than melanoma, but early detection leads to successful treatment.

Treatment of Non-Melanoma Skin Cancer

• Surgery is the most common treatment.
• Chemotherapy: Applied to the skin as an ointment or cream.
• Radiation therapy: Used for skin cancers near the eyes, nose, or forehead.
• MCC treatment: Surgery, radiation therapy, chemotherapy, and immunotherapy.

Melanoma Facts

• Melanoma is the most serious type of skin cancer.
• In 2019, approximately 15,229 diagnoses were expected, nearly one diagnosis every half hour.
• It is the third most common cancer in Australian men and women.
• If detected early, more than 90% of melanoma cases can be successfully treated with surgery.
• Australia has one of the highest melanoma rates in the world.
• Melanoma is the most common cancer in young Australians (15-39 year olds), with incidence also high and increasing in people over 60.
• In Australia, 1 person dies from melanoma every 5 hours.
• Most melanomas are caused by prolonged and repeated exposure to UV radiation.
• Melanoma makes up 2% of all skin cancers but accounts for 75% of skin cancer deaths.

Types of Melanoma

• Superficial spreading melanoma (~70% of melanomas).
• Nodular melanoma (~15% of melanomas).
• Acral lentiginous melanoma.
• Lentigo maligna melanoma.
• Amelanotic and Desmoplastic melanoma.
• Ocular melanoma.
• Mucosal melanoma.

Diagnosing Melanoma

• ABCDEs of melanoma:
  • Asymmetry.
  • Border irregularity.
  • Color variation.
  • Diameter > 6 mm.
  • Evolution.

Diagnosing Melanoma - Procedures

• Removing the mole.
• Checking lymph nodes via:
  • Fine needle biopsy.
  • Sentinel lymph node biopsy.
• Further tests:
  • Ultrasound.
  • CT scan.
  • MRI scan.
  • PET-CT scan.

Stages of Melanoma and Treatment Options

• Stage 0 (In situ): Tumor confined to the epidermis. Treatment: Surgical removal (wide local excision).
• Stage I: Melanoma up to 2 mm thick without ulceration, or up to 1 mm thick with ulceration. Treatment: Surgical removal; sentinel lymph node biopsy may be considered.
• Stage II: Tumors thicker than 2 mm with or without ulceration, or between 1-2 mm with ulceration. Treatment: Surgical removal; sentinel lymph node biopsy may be considered.
• Stage III: Any thickness, spread to nearby lymph nodes or tissues. Treatment: Surgical removal; lymph node dissection; drug and radiation therapies.
• Stage IV: Any thickness, metastases to distant lymph nodes or sites. Treatment: Surgery or systemic therapies (immunotherapy, targeted therapy); radiation therapy may also be used.

Treatment for Early Melanoma

• Surgery: Wide Local Excision.
• Removing lymph nodes:
  • Sentinel Node Biopsy.
  • Lymph Node Dissection.
• Additional treatment:
  • Immunotherapy.
  • Targeted therapy.

How to Make a Melanoma

• Key pathways involved: WNT5A, hypoxia, TNF, GPCR, FAK, RTK, PI3K, NRAS, BRAF, AKT, MEK, MAPK, NFKB, JNK, and others.
• Processes affected: Apoptosis, proliferation, EMT, and migration.

Genetic Changes in Melanoma

• Common genetic changes:
  • $CDKN2A$ (p16, ARF): Deletion, methylation, or mutation. Found in 50-78% of melanomas.
  • $BRAF$: Activating mutation. Found in 47% of melanomas.
  • $TBX2$: Amplification. Found in 43% of melanomas.
  • $APAF1$: Methylation. Found in 42% of melanomas.
  • $CDKN2B$ (p15): Deletion. Found in 36% of melanomas.
  • $PTEN$: Mutation or deletion. Found in 17-28% of melanomas.
  • $NRAS$: Activating mutation. Found in 21% of melanomas.
  • $APC$: Methylation (+1 mutation). Found in 16% of melanomas.
  • Other genes: $KIT$, $MITE$, $STK11$, $TP53$, $CTNNB1$, $PTPRD$, $RB1$, $MYC$.

Melanoma Susceptibility Genes

• Genes and their roles:
  • $CDKN2A$: Encodes P16INK4a and P14ARF, cell cycle regulators. Mutation prevalence: ~20-40% of families.
  • $CDK4$: Cell cycle regulator. Mutation prevalence: ~1% of families.
  • $TERT$: Catalytic subunit of telomerase, telomere elongation. Mutation prevalence: 17 families.
  • $POT1$: Telomere maintenance. Mutation prevalence: 2 families.
  • $MC1R$: Melanin synthesis and melanocyte proliferation. Penetrance: Intermediate. Mutation prevalence: 14 families.
  • $MITF$: Melanocyte development and differentiation. Penetrance: NA.

Risk Factors for Melanoma and Metastatic Melanoma

• Major risk factors:
  • Light skin, light-colored hair (blond, red), or light-colored eyes (blue, green).
  • Skin prone to burning easily.
  • Multiple blistering sunburns as a child.
  • Family history of melanoma.
  • Frequent sun or UV exposure.
  • Certain genetic mutations.
  • Exposure to environmental factors.
• Factors associated with increased metastasis:
  • Male gender.
  • Primary tumor thickness > 4 mm.
  • Nodular melanoma.
  • Ulceration of the primary tumor.

Metastatic Melanoma Symptoms

• General symptoms:
  • Fatigue.
  • Swollen or painful lymph nodes.
  • Weight loss.
  • Loss of appetite.
  • Trouble breathing or a persistent cough.
  • Bone pain.
  • Headaches.
  • Seizures.
  • Swelling of the liver.

Metastatic Melanoma Treatment

• Approaches include:
  • Drug Therapy: Immunotherapy, Targeted therapy, Chemotherapy.
  • Radiation therapy.
  • Surgery.

Immunotherapy

• Mechanism: Blocks PD-L1 or PD-1 to allow T cell killing of tumor cells.
• Checkpoint inhibitors (e.g., Ipilimumab, Nivolumab, Pembrolizumab) increase the immune system’s ability to kill cancer cells.
• Side effects: Inflammation, tiredness, joint pain, diarrhea, and skin problems.

Targeted Therapy

• Attacks specific features of cancer cells to stop growth and spread.
• Targeted therapy: E.g., BRAF inhibitors (Dabrafenib, Vemurafenib) and MEK inhibitors (Cobimetinib, Trametinib) for patients with BRAF mutations.
• Response rate to combined BRAF/MEK inhibition is about 70% or higher.

Chemotherapy

• Uses drugs to destroy cancer cells.
• Less often used due to the effectiveness of immunotherapy and targeted therapy.
• Dacarbazine (DTIC) and Temozolomide (Temodar) can shrink melanoma for about 12-15% of patients.
• Side effects: Fatigue, infection risk, nausea, vomiting, nail changes, appetite loss, diarrhea, nerve damage, and hair loss.

Radiotherapy

• Uses x-rays to target and kill cancer cells by damaging their DNA.
• Treatment must be carefully planned to allow normal cells to repair themselves and minimise side effects.
• Common side effects: Tiredness and skin redness/soreness in the treatment area.

Surgery for Advanced Melanoma

• Used to remove melanoma from the skin, lymph nodes, or other organs.
• Drug therapy can be neoadjuvant (before surgery) or adjuvant (after surgery).

Challenges in Metastatic Melanoma Treatment

• Identifying biomarkers for patient selection.
• Overcoming primary and acquired resistance.