Week 4

• Breast Cancer Risk Factors:

  • Germline mutations increase the risk by 5% to 10%
  • First-degree relatives with breast cancer increase the risk by 15% to 20%
  • Race/ethnicity is correlated with breast cancer risk, with non-Hispanic white women having increased incidence
  • Age increases the risk, peaking at 70 to 80
  • Menarche at ages younger than 11 years increases the risk by 20%
  • Late menopause increases the risk
  • A full-term pregnancy before the age of 20 halves the risk
• Other Breast Cancer Risk Factors:

  • Benign breast disease increases the risk
  • Estrogen exposure, menopausal hormone therapy, and breast density increase the risk
  • Radiation exposure and carcinoma of the contralateral breast or endometrium increase the risk
  • Diet high in alcohol, obesity (post-menopausal), lack of exercise, and lack of breastfeeding increase the risk
  • Environmental toxins exposure increases the risk
• Breast Cancer Aetiology:

  • Genetic factors account for 12% of breast cancer cases, including inherited mutations in BRCA1, BRCA2, TP53, and CHEK2
  • Oestrogen exposure plays a role, with oophorectomy decreasing the risk by 75% and hormone replacement therapy increasing the risk
• Breast Cancer Classification:

  • In-situ disease includes lobular and ductal types with different grades
  • Invasive disease includes Invasive Lobular Carcinoma (ILC) and Invasive Ductal Carcinoma (IDC), NST, as well as special types
• Breast Cancer Types:

  • Infiltrating Ductal Carcinoma is characterized by irregular glands infiltrating fibrous stroma and fat
  • Infiltrating Lobular Carcinoma is the second most common type, with multifocality, bilaterality in 15-20% of cases, and a tendency to metastasize to serous cavities
  • Tubular Carcinoma is characterized by tubules comprising over 90% of the tumor, desmoplastic stroma, and has an excellent prognosis
• Breast Cancer Prognostic Factors:

  • Tumor histological type, grade, size, spread (lymph node status), and biological markers are important factors
  • Tumor grade is classified as Grade 1 (3-5), Grade 2 (6-7), and Grade 3 (8-9)
• Breast Cancer TNM Staging:

  • Staging considers tumor size and spread, with Stage 0 to Stage III indicating progressively worse local and nodal disease, and Stage IV indicating metastatic disease
  • TNM classification includes T (Tumour), N (Lymph Node), and M (Metastasis) categories
• Breast Cancer Biological Markers:

  • ER, HER2, and HER2 - FISH are important markers
  • The best prognosis is associated with ER+HER2- expression
• Breast Cancer Molecular Subtypes:

  • Luminal A has the highest ER expression
  • Luminal B has low-moderate ER expression
  • Luminal C has low-moderate ER expression plus a set of novel genes
  • Her2 (ErbB2) subtype shows overexpression of Her2
  • Basal subtype expresses genes typical of basal/myoepithelial cells
• Breast Cancer Molecular Subtypes and Survival:

  • Basal and Her2 positive subgroups have the shortest survival time
  • Luminal B and C subtypes exhibit worse outcomes than Luminal A
• Cervical Intraepithelial Neoplasia (CIN) is a precursor lesion to Squamous Cell Carcinoma (SCC), which is the commonest type of cervical cancer
• CIN I to CIN III represent increasing levels of dysplasia
• Squamous Cell Carcinoma (SCC) of the cervix has a focus of invasion in the squamous epithelium and may present with keratin pearls
• Cervical carcinoma is sexually transmitted and is caused by the Human papillomavirus (HPV), with high-risk types including 16, 18, 31, 33, 35, and 55
• High-risk HPV types have a higher affinity for p53 and RB
• Histological feature seen on H&E staining of squamous cell carcinoma includes Koilocytes, Ki-67, and P16 IHC staining
• Other oncogenic microbes associated with cancer include:

  • Epstein Barr Virus: associated with Burkitt lymphoma, B cell lymphoma, Nasopharyngeal lymphoma
  • Hepatitis B/C: associated with Hepatocellular carcinoma
  • HTLV-1: associated with T cell lymphomas
  • Helicobacter pylori: associated with Gastric lymphomas
• Colorectal Cancer is majority glandular (adenocarcinoma) and is a well-characterised multistep process
• Most colorectal cancers arise in adenomas, which are benign glandular neoplasms (dysplastic) and not cancer
• There are two main types of adenomas:

  • Tubular adenoma
  • Villous adenoma, which exhibit dysplasia with characteristics such as nuclear hyperchromasia, raised N:C ratio, and pseudostratification
• Adenomas are precursor lesions to adenocarcinoma, with the likelihood of progression influenced by factors such as type (villous > tubular), size, degree of dysplasia (high-grade > low-grade), and molecular pathways like APC multistep progression and microsatellite instability
• 80% of sporadic colon cancers are associated with the APC gene, with germline mutations leading to the development of hundreds of adenomas at an early age and invasive carcinoma after approximately 25 years
• Microsatellite instability (MSI) is present in 10-15% of sporadic colorectal cancers and is associated with germline mutations in mismatch repair genes, leading to Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome
• Colorectal adenocarcinoma is characterized by glandular structures infiltrating a desmoplastic stroma
• In staging colorectal cancer, TNM classification is compared to Duke’s classification, where T4 indicates invasion into adjacent organs
• The peak age for colorectal cancer is 60-70 years old, with dietary factors such as low fiber, high intake of red meat, high refined carbs, and fat associated with increased risk. Rates are higher in the US, Australia, New Zealand, and Europe, and lower in South America, India, Africa, and South Central Asia
• HNPCC is due to a germline mutation of mismatch repair genes, making the statement TRUE
• Lung Cancer is the most common cause of cancer mortality
• The major risk factor for lung cancer is smoking
• Lung cancer is increasing in women, which may reflect smoking patterns
• The outcome for lung cancer is universally poor, with a 5-year survival rate of approximately 15%
• Epidemiological, clinical, and experimental evidence link smoking with lung cancer
• Major carcinogens linked to lung cancer include polycyclic aromatic hydrocarbons, phenol derivatives, and radioactive elements
• Non-small cell lung cancer includes:

  • Squamous cell carcinoma (25-40%)
  • Adenocarcinoma (25-40%)
  • Large cell carcinoma (10-15%)
• Small cell lung cancer accounts for 20-25% of lung cancers
• Squamous Cell Carcinoma (SCC) is proximal and associated with precursor squamous metaplasia and squamous dysplasia
• Molecular changes in SCC include p53 mutation, EGFR overexpression, Her2/neu overexpression, CDKN2A (loss p16), and FGFR1 amplification
• Adenocarcinoma is distal and increasing, especially in women, related to low tar cigarettes, and metastasizes widely
• Less frequently related to smoking, adenocarcinoma has "gain of function" mutations in EGFR, ALK, MET, and RET
• Highly aggressive neuroendocrine tumors are associated with smoking and have molecular changes such as p53, RB (~100%), MYC amplification