Week 6 - Lung Cancer Flashcards
Outline lung cancer.
• Most common internal cancer (visceral/internal malignancy).
• Kills more people than all other internal cancers combined (very common, significant in general practice).
• Increasing incidence in developing countries and females (more smoking). Decreasing incidence in developed countries.
• 90% of lung cancers are related to smoking (however, not all smokers develop cancers and not all those that develop cancer are smokers). Other aetiologic agents but smoking most significant.
• 11% of smokers → lung cancer. Also develop other diseases such as COPD, bronchiectasis.
• Persisting poor prognosis ~5% 5y survival (high death rate due to late detection - by the time they produce symptoms → lung cancer spread).
• 60 fold increased risk among habitual heavy smokers (2 packs/day/20y).
• >100 fold if combined with other risk factors (asbestos, coal, radon etc.)
• Dysplastic (irregular, abnormal) cells in sputum of 96.7% of smokers vs. 0.9% in non-smokers - smoking causes 3p deletion → deletion of short arm of chromosome 3. Commonly seen in smokers, seen in normal bronchial epithelium. Fertile soil for other mutations and cancers to develop.
• 95% of lung cancers are bronchogenic carcinomas - due to cigarette smoke occurring in major bronchi (5% carcinoid, harmartoma, mesothelioma etc.)
• Smoke carcinogens (strong carcinogenesis):
- Initiators - benzo[o]pyrenes.
- Promoters - phenol derivatives.
- Radioactive substances - polonium, C14, K40.
Outline the aetiology of lung cancer.
- Smoking* (11% of heavy smokers develop cancer).
- Occupational exposure (industry/chemical exposures) - asbestosis, nickel, chromates, mustard gas, arsenic coal-tar distillation.
- Fibrosis/scarring - TB, pneumoconiosis, honeycomb lung - adenocarcinomas more common (scar cancers - past history of pneumonia etc. resulting in scarring → adenocarcinoma).
- Radioactive gases - radon, atomic bomb survivors.
- Genetic predisposition - P450 gene polymorphisms.
- Idiopathic.
Explain the pathogenesis of lung cancer.
• Injury (COPD) → carcinogens → initiation → promotion → cancer.
- Smoking/carcinogens.
- 3p/EGFR mutations.
- Dysplasia.
- More mutations (KRAS, C-Myc).
- Infiltration.
- Spread.
- Metastases (p53).
- Cigarette smoke → continuous damage/injury to respiratory ciliated epithelium → coverts ciliated columnar epithelium to squamous epithelium (metaplasia) → then develops irregularity of nucleus (dysplasia) → leads to loss of cilia, accumulation of mucus. Secondary infection, continuous inflammation, emphysema/CB (COPD).
- Further damage and continuous cell division exposes nuclear material to mutations → mutations lead to cells becoming abnormal and developing malignant potential → starts infiltrating and spread in body.
- Starts typically with 3p deletion in smoker, EGFR mutation in non-smoker. Multiple mutations occur on the basis of these 2 mutations. Each mutation adds a malignant feature e.g. spreading, infiltration, metastasis → leads to tumours.
- Treatment based on the type of mutation (personalised medicine).
- More mutations (e.g. KRAS, C-myc) lead to infiltration, spread and metastases (usually associated with p53).
• Basal cell hyperplasia → squamous metaplasia → squamous dysplasia → carcinoma in situ.
Describe the classification of lung cancer.
- The 4 major (95%) histological types of carcinomas of the lung are adenocarcinoma, squamous cell carcinoma, small cell carcinoma and large cell carcinoma.
- In some cases, there is a combination of histologic patterns (e.g. SCC and adenocarcinoma).
- Squamous cell and SCC show the strongest association with smoking.
- Adenocarcinomas are the most common primary lung tumour and the most common primary tumours arising in women, non-smokers and persons younger than 45yo.
• Most common lung tumours (95%) known as bronchogenic carcinomas (start in bronchus). 2 classifications:
- SCC (20%) - neuroendocrine cells which are in the bronchus, strong association with smoking and 3p deletion.
- NSCC (80%) - adenocarcinoma (most common) and squamous cell carcinoma.
• Majority of cases due to smoking, although adenocarcinomas can be seen in non-smokers (as well as SCC and squamous). Poor prognosis - at diagnosis, 50% of patients already have distant metastatic disease, while a fourth have a disease in the regional lymph nodes.
• The remaining 5% constitute a miscellaneous group that includes carcinoids, mesenchymal malignancies (e.g. fibrosarcoma, leiomyomas), lymphomas, and a few benign lesions.
Why are lung cancers classified?
- The key reason for the historical distinction was that virtually all SCCs have metastasised by the time of diagnosis and hence are not curable by surgery. Therefore, they are best treated by chemotherapy with/without radiation.
- By contrast, NSCCs were more likely to be resectable and usually responded poorly to chemotherapy. However, therapies are now available that target mutated gene products present in the various subtypes of NSCC, mainly in adenocarcinomas. Thus, NSCCs must be sub classified into histologic and molecular subtypes.
• Location is also important:
- SCC start in hilum → gradually spread around the bronchi (infiltrating tumour).
- Squamous start in hilum (central tumour) → expands rather than infiltrates (expanding tumour).
- Adenocarcinomas typically occur away from the centre (peripheral tumours) → also expands
What is a hamartoma?
- Most common benign tumour.
- Small, spherical, discrete.
- Often shows up as a so-called coin lesion on chest radiographs.
- Consists mainly of mature cartilage but this is often admixed with fat, fibrous tissue and blood vessels in various proportions.
- Clonal cytogenic abnormalities have been demonstrated indicating that it is a benign neoplasm.
Describe the morphology of small cell carcinomas.
Gross: • Grey white, diffuse infiltration, hilar. • Spread around bronchi. • Infiltrative. • Early spread.
Microscopy:
• Irregular dark blue cells in sheets.
• Pleomorphic cells with irregular nuclei.
• Necrosis (no glands or keratin pearls).
• Neuroendocrine cells - produce tumour markers (ACTH).
Identify the key features of small cell carcinomas.
- Central/hilar tumour.
- Neuroendocrine cells → paraneoplastic syndrome.
- Strong smoking association (3p deletion).
- Infiltrative - spread early along bronchi.
- Small cells, scanty cytoplasm, large moulded dark nucleus (oat cell ca).
Describe the morphology of squamous cell carcinomas.
Gross:
• Grey white, nodular infiltrating in hilum.
• Arising from major bronchus or trachea.
• Infiltrating into surrounding region.
• Spread to lymph nodes or extrapulmonary.
Microscopy: • Irregular cells forming irregular clusters. • Pleomorphic with irregular nuclei. • Keratin formation - epithelial pearls. • Infiltration, invasion and necrosis.
• Start from bronchus but expand rather than infiltrate. Expansion into surrounding areas instead of along lines of bronchus. Clearly defined (can put a line around the cancer) unlike SCC.
Identify the key features of squamous cell carcinomas.
- Central/hilar tumour.
- More in men, smokers.
- Keratin pearl formation.
- 3p deletions.
Describe the morphology of adenocarcinomas.
Gross:
• Grey white, nodular - peripheral/hilar.
• Central scar, women/non-smokers.
• Expanding tumour.
• Spread to lymph nodes or extrapulmonary.
Microscopy:
• Pleomorphic cells with irregular dark nuclei.
• Forming irregular glands (grade).
• Infiltration and invasion into surrounding tissue.
• Areas of necrosis.
Identify the key features of adenocarcinomas.
- Typically in women, non-smokers.
- Previous scar.
- Gland formation.
- EGFR mutations.
Outline the staging and grading of lung cancer.
Staging: • Spread from origin. Examines the clinical progression of the cancer using the 'TMN.' • T - tumour (T0, 1, 2, 3, 4). • N - node (N1, 2, 3). • M - metastasis (M0, 1).
Grading:
• Resemblance to normal cell. Based upon microscopic examination of cell differentiation.
• Low grade (normal) - well differentiated.
• High grade (abnormal) - poorly differentiated.
Identify the clinical features of lung cancer.
- Weight loss (cachexia) - due to cytokine production (IL-6, IL-8, PIF).
- Cough - due to obstruction and necrosis of bronchus.
- Haemoptysis - due to invasion and necrosis of lung stroma. Cancer proteases breakdown surrounding tissue/blood vessels → haemorrhage (cancer cells produce proteolytic enzymes and infiltrate into surrounding tissues causing haemorrhage).
Local:
• Obstruction, effusion - cancer obstructs distal portion of lung → undergoes necrosis, bronchiectasis, pneumonia, pleural effusion, dead tissue inflammation. Obstruction of bronchus also causes atelectasis.
• Pneumonia
• Bronchiectasis.
• Atelectasis, haemoptysis.
• SVC syndrome - infiltration into supraclavicular node can cause obstruction of SVC.
• Pancoast tumour - tumour in upper part of lungs obstructing and destroying the first 2 ribs.
• Horner’s syndrome - involvement of sympathetic nerves due to tumour.
Systemic:
• Cachexia - weight loss, loss of appetite.
• Paraneoplastic syndrome - small cell cancers (and occasionally squamous cell) can give rise to hormones → produce clinical features → paraneoplastic syndrome.
• Clubbing.
• Bone pain - metastasis to bone → pain, fractures.
• Epilepsy - metastasis to CNS → epilepsy.
Outline the investigations for lung cancer.
• Imaging: X-ray, US, MRI, CT, PET (mainstay)
- Central - infiltrative - SCC.
- Central - expanding - squamous.
- Peripheral - expanding - adenocarcinoma.
- Exceptions can occur e.g. adenocarcinoma centrally and squamous peripherally.
- Cytology - sputum, bronchial lavage (diagnose/classify cancer).
- Bronchoscopy, thoracotomy.
- Biopsy - needle, excision.
- Tumour markers - epithelial, neuro, endo (epithelial, neuroendocrine and hormone markers help in diagnosing lung cancer).
Diagnosis and staging: 1. Possible lung cancer. 2. Chest radiograph (abnormal). • Central - Sputum cytology - Bronchoracic biopsy. - Transthoracic biopsy. • Peripheral - CT guided transthoracic biopsy. - Thoracoscopy - Thoracotomy 3. Lung cancer diagnosed.
