L15 Melanoma & Cervical Cancer

• Cervical and skin cancers including melanoma


  Learning outcomes:

  
• Pathogenesis of cervical and skin cancers including melanoma

  Understand the pathogenesis

  
• Carcinogens


  Mechanism of action and effect of specific carcinogens
• Multistage carcinogenesis for each cancer

  Understand the progression
• Effect of mutations on cell cycle dysregulation

  Understand the effect
• Skin cancer


  • Melanoma
  • Carcinogen is (usually) UV light

  
• Cervical cancer


  Role of HPV
• Normal skin has melanocytes that make the pigment melanin, basal cells that divide to form keratinocytes, and keratinocytes that make keratin for protection
• Carcinogens


  • Chemical (asbestos, coal tars, hardwood sawdust, tobacco smoke, aromatic hydrocarbons)
  • Physical (non-ionising radiation, ionising radiation, oncogenic viruses)
• UV rays induce


  Increased incidence of squamous cell carcinoma, basal cell carcinoma, and malignant melanoma of the skin

  
• Transformation of melanocytes into melanoma

  1. UV light causes DNA damage by forming pyrimidine dimers

  2. Normally repaired by nucleotide excision repair pathway
• Atypical moles (dysplastic naevi)


  Have an indistinct border, may be inherited, may develop into melanoma
• Melanocytic Tumour Progression


  • Dysplastic naevi documented in families prone to malignant melanoma
  • Some people have inherited mutation in CDKN2A (INK4A) which encodes p16, a cell cycle regulator gene

  
• Malignant melanoma


  • Ongoing damage from multiple hits of carcinogens, usually UV light
  • May damage proto-oncogenes and tumour suppressors like BRAF, p53, leading to dysregulation of cell signalling and cell cycle
• Mutations in melanoma


  • RAS
  • PTEN
  • MDM2
  • p14
  • p53
  • BRAF
  • CDK4
  • p16
• Radial Growth Phase (RGP) Melanoma


  In situ melanoma within the basement membrane, 100% cure with adequate excision, without potential to metastasise
• Vertical Growth Phase Melanoma


  Has potential to metastasise
• ABCDE checklist for mole and melanoma assessment

  Asymmetry, Border irregularity, Colour variation, Diameter increase, Elevation (new) of lesion
• Oncogenic DNA viruses like HPV, JC viruses, EBV, and HSV can integrate into host cell genome and remain latent for years, especially with immunosuppression

  
• Carcinoma of the uterine cervix

  Death rate has declined by two-thirds to its present rank as the eighth leading cause of cancer mortality
• Cervical Dysplasia - In Situ

  Non-invasive stage that may last 20 years or as short as several months, represents a continuum of morphologic change with indistinct boundaries, do not invariably progress to cancer and may spontaneously regress
• Progression of Dysplasia - disordered growth

  1. Dysplasia starts in the lower third of the epithelium (low grade) and spreads upwards in high-grade dysplasia

  2. Invasion through the basement membrane is due to further acquisition of genetic mutations
• Koilocytes


  Squamous epithelial cells that look different due to HPV infection, with larger nuclei compared to cytoplasm, darker staining, and a clear area around the nucleus

  
• SIL (Squamous Intraepithelial Lesion)

  Abnormal cells with increased nucleus to cytoplasm ratio, hyperchromatic nuclei, and loss of glycogen
• Squamous cell carcinoma contains HPV in 95% of cases, with HPV-16 (50%) and HPV-18 (20%) being the most common high-risk types

  
• HPV mechanism


  • E6 binds to p53, preventing apoptosis of damaged cells and loss of cell cycle control
  • E7 interferes with transcription of p53, binds to RB stopping it from limiting cell growth, and inactivates p21 leading to loss of cell cycle control
• From July 2023, the primary test for cervical screening will change to an HPV PCR test, done every 5 years rather than 3
• Gardasil vaccine


  Targets HPV 6, 11, 16 and 18, contains virus-like particles that elicit a strong T- and B-cell response and development of antibodies