L16 Lung Cancer

• Lecture 13 - Neoplasia 1

  Monday, April 15
• Lecture 14 – Neoplasia 2


  Wednesday, April 17
• Lecture 15 – Neoplasia 3

  Monday, April 22
• Lecture 16 – Neoplasia 4


  Wednesday, April 24
• Lung Cancer


  • Recap of respiratory system
  • Etiology of Lung Cancer
  • Definition and types of Lung Cancer
  • Macro pathology
  • Histopathology
  • Metaplasia to dysplasia sequence
  • Multistage Carcinogenesis
  • Paraneoplastic syndromes
  • Secondary lung cancer
  • Staging of lung cancers – TNM system
  • Malignant Pleural Mesothelioma
• Respiratory System


  • Bronchus
  • Bronchiole
  • Lung Histology – Epithelial type?

  
• Epithelium is ciliated pseudostratified columnar (PSC)
• Bronchiole = ciliated simple cuboidal
• Alveolus = squamous
• Etiology


  • ~80% of lung cancers occur in smokers or those who have recently stopped smoking
  • Only 11% of heavy smokers develop cancer
  • Heavy smoking (2 packs/day for 20 yrs) increases the risk x60 – this is the major risk factor
  • Females are more susceptible to carcinogenic effect of smoking
  • Cessation for 10 years or more reduces the risk but never to 'normal' (mutations sustained in bronchial epithelium persist)
  • Second-hand smoking doubles the risk of non-smokers
• Other Risk factors


  • Industrial exposure
  • Asbestos
  • Chemicals
  • Radiation
  • Scarring from other diseases
  • Radiation from Radon (this is a naturally occurring radioactive particle)
• Vaping and lung cancer - A review of current data and recommendations
• 1. cigarette devices and vaping fluids contain both definite and probable oncogenes including nicotine derivatives (e.g. nitrosnornicotine, nitrosamine ketone), polycyclic aromatic hydrocarbons, heavy metals (including organometal compounds) and aldehydes/other complex organic compounds.
• Various studies demonstrate in vitro transforming and cytotoxic activity of these derivatives.
• Five-year survival trend


  • Prostate cancer
  • Breast cancer
  • Colorectal cancer
  • Lung cancer
• Survival rates for lung cancer are generally low
• Survival rates vary depending on stage at diagnosis. The later the stage of diagnosis the lower the survival rates tend to be.
• Lung Cancer - Definition

  • Invasive malignant neoplasms derived from epithelia
  • Bronchi (PSC)
  • Bronchioles (cuboidal)
  • Alveoli (squamous)
• Types of epithelia


  • Projecting into the lumen
  • Leading to diffuse thickening of the wall and narrowing of the lumen
  • Eroding the surface epithelium and variable amounts of subepithelial tissue
• Bronchogenic Carcinomas


  • Adenocarcinoma (male 37%, female 47%)
  • Squamous cell carcinoma (male 32%, female 25%)
  • Small cell carcinoma (males 14%, females 18%)
  • Large cell carcinoma (males 18%, females 10%)
• Adenocarcinoma


  • A malignant epithelial tumor with glandular differentiation or mucin production
  • May be preceded by a precursor lesion called atypical adenomatous hyperplasia
• Squamous cell carcinoma


  • Preceded by changes in airway induced primarily by tobacco smoking
  • The carcinoma begins in the epithelial cells lining the bronchi that have undergone squamous metaplasia due to the carcinogen
  • Progresses to a malignant epithelial tumor showing keratinization and/or intercellular bridges
• Squamous cell carcinoma progression

  1. Normal

  2. Metaplasia

  3. Dysplasia
• Bronchial Dysplasia is a presumed precursor lesion of SCC
• Invasive Squamous Cell Carcinoma (SCC) Histology

  • A-Invasive SCC forming keratin pearls (left)
  • B-Keratin pearls and intercellular bridges
• Small Cell Carcinoma


  • Also called 'oat cell'
  • Small undifferentiated cells
  • Moulding
  • Hyperchromatic
  • Pleomorphic
  • Densely packed with very little cytoplasm (high N:C ratio)
  • Lots of mitoses (so rapidly proliferating)
  • Cell of origin is thought to be neuroendocrine progenitor cells in bronchial epithelium
  • Often involves the lymphatics
  • Spreads along the bronchi
  • Common mutations: p53, RB (retinoblastoma), genes on chromosome 3p, MYC, c-KIT, and BCL-2 (involved in control of apoptosis)
• • Narrowed lumen
  • Infiltrating tumour
  • Mets in lymph nodes
• Multistage carcinogenesis – Carcinoma

  1. Normal

  2. Cancer

  3. Increasing Mutations

  4. EGFR mutation

  5. KRAS mutation

  6. Adenocarcinoma
• Molecular Pathogenesis


  • An accumulation of genetic mutations and epigenetic alterations in cells exposed to carcinogens (mainly tobacco-smoke)
  • Mutations in genes controlling cell growth (i.e. tumour suppressors and oncogenes) -> cells with a proliferative advantage -> invasion
  • Common mutations in oncogenes (genes whose products promote cell growth and proliferation) in Lung cancer: KRAS, EGFR, c-MYC, c-KIT and c-MET
  • Common mutations in Tumour suppressor genes (whose products limit or block damaged cell growth and proliferation) include: p53, RB1, p16(INK4a) and several loci on chromosome 3p
• Histologic and Molecular Changes Pulmonary Squamous Cell Carcinoma
• Large cell carcinoma


  • Poorly differentiated malignant neoplasm lacking squamous or glandular differentiation
  • The tumor cells are highly atypical, with large, pleomorphic nuclei, with prominent nucleoli, and abundant cytoplasm
  • There are usually many mitoses
  • Usually present as large masses in the peripheral lung fields
• Clinical Presentation in Lung cancer

  • Cough, sometimes with blood (haemoptysis)
  • Shortness of breath (dyspnea)
  • Post-obstructive pneumonia (an infection of lung parenchyma secondary to bronchial obstruction)
  • Pain from pleural or chest wall invasion by peripheral tumors
  • Weight loss
  • Tracheal or oesophageal obstruction (due to thoracic spread)
  • Hoarseness due to recurrent laryngeal nerve involvement

  
• Paraneoplastic syndromes


  • Refer to symptom complexes that can occur with tumours but are not directly related to the cancer mass effects or invasion
  • Common in Lung Cancer
  • Classic examples are endocrinopathies due to ectopic hormone production by the tumor
• Secondary Lung cancer


  Primary lung cancers tend to metastasise to Liver, Adrenals, Bone, Skin
• Origin of Cancer cells in metastasis can be identified by tissue specific markers
• Malignant Pleural Mesothelioma (MPM)


  • 80-90% of people diagnosed with malignant pleural mesothelioma have been exposed to asbestos
  • 20-40 year latency following inhalation
  • Exposure to asbestos AND smoking increases the risk to greater than just the addition of each of the two
• Asbestos Exposure


  • Contributes to: Lung cancer, Asbestosis (lung fibrosis), Mesothelioma (malignant tumor of the pleura)
  • Exposure: Mining, construction and demolition engineers and boiler makers
  • Exposure to asbestos and smoking increases the risk of lung cancer greater than the individual risk factors added together
• Asbestos body within a macrophage in the lung
• Lung Cancer Summary


  • Cigarette smoking is the main cause of Lung Cancer
  • Particularly for a long time
  • Leads to a change in the epithelium (i.e metaplasia) to adapt to the increased cellular stress
  • Usually to squamous cell
  • Then to dysplasia
  • Bronchogenic carcinomas
  • Adenocarcimoma
  • Squamous cell carcinoma
  • Small cell carcinoma
  • Large cell carcinoma
  • Paraneoplastic syndromes
  • Secondary lung cancer
  • Staging of lung cancers – TNM system
  • Malignant Pleural Mesothelioma
• HEDC evaluation - I would appreciate your taking 5 minutes to complete this