CLI Week 6 Flashcards
pathology of smoking and smoking related disorders
Smoke carcinogens:
- Initiators: benzopyrenes
- Promoters: phenol derivatives
- Radioactive substances: polonium, C14, K40
Pathogenesis:
- Normal trachea: ciliated pseudostratified simple columnar à smoke injures epithelium à metaplasia to stratified squamous epithelia (protective mechanism to reduce further injury) à mucous dysplasia, loss of cilia and accumulation of mucous à secondary infections à COPD
- Further damage from inhaled carcinogens and continuous cell division à mutations in nucleus (3p/EGFR) à dysplasia à more mutations (KRAS, C-Myc) à infiltration à spread à metastases (p53)
- NOTE: non smokers can get cancer from EGFR deletions ; smokers more commonly have 3p deletion
- Treatment is personalised to specific mutation for patient
pathology of Primary lung cancers
Classification of lung tumours (bronchogenic carcinomas account for 95%):
- SCLC- small cell carcinoma
- NSCLC- non small cell lung cancers
- SCC- squamous cell carcinoma
- Adenocarcinoma
Biology of lung cancer
- Grading: microscopic features – how much does the cell resemble normal tissue for that location
- Low grade: well differentiated cells for its tissue, clear glands (if applicable)
- High grade: no structures resembling tissue, poorly differentiated from more mutations
- Staging: clinical features, degree of growth and spread
- T: tumour size and level of infiltration (T0-T4)
- T1: _<_3cm, no invasion, proximal to lobar bronchus
- T2: >3cm, main bronchus, invasion of visceral pleura
- T3: any size, main bronchus, invasion of chest wall/ diaphragm/ parietal pericardium
- T4: any size, invasion of mediastinum/ trachea/ vertebral body/ carina/ oesophagus
- N: node involvement
- N1- Hilar node: ipsilateral/ peribronchial
- N2- mediastinal node: subcarinal/ ispilateral
- N3- contralateral mediastinal/ scalene / supraclavicular node
- M: metastasis (MO absent M1 present)
- T: tumour size and level of infiltration (T0-T4)
Clinical features and complications of lung cancer:
Local
Systemic
- Obstruction, effusion
- Pneumonia
- Bronchiectasis: yellow purulent sputum, foul smelling
- Atelectasis, haemoptysis
- SVC syndrome (Pemberton’s)
- Pancoast tumour (apical- results in Horner’s)
- Horner’s syndrome- sympathetic nerves (anhydrosis, miosis, ptosis)
- Cachexia
- Paraneoplastic syndrome (ACTH, ADH)
- Clubbing
- Bone pain (METs)
- Epilepsy (METs)
Investigations
- CXR, MRI, CT, PET
- Cytology: sputum and bronchial lavage
- Biopsy: excision/ needle
- Tumour markers: epithelial, neuro, endo
details on major types: Scc, small cell cancer and adenocarcinoma
Small cell carcinoma
Squamous cell carcinoma
Adenocarcinoma
Category
Small cell cancer
Non small cell cancer
Non small cell cancer
At risk
Males
Smokers- 3p deletion
Males
Smokers
Females
Non smokers
imaging
Central, infiltrative (diffuse- spread early along bronchi)
Hilar opacity
Central, expanding (localised)
Clear border, nodular tumour
Peripheral, expanding (localised)
Opacity in periphery
Cytology
‘oat cells’ scanty cytoplasm, no glands or keratin
Dark blue
Pink cells: keratin
Blue nucleus, cytoplasm and vacuoles à mucin (glands)
Pale blue
Microscopy
Irregular dark blue cells in sheets
Pleomorphic cells with irregular nuclei
Necrosis (no gland or keratin pearl)
Neuroendocrine- (ACTH)
Irregular cells forming irregular clusters
Pleomorphic with irregular nuclei
Keratin formation – epithelial pearls
Infiltration, invasion and necrosis
Pleomorphic cells with irregular dark nuclei
Forming irregular glands
Infiltration and invasion into surrounding tissue
Areas of necrosis
Gross specimen
Grey white, diffuse infiltration, hilar
Spread around bronchi
Infiltrative
Early spread
Grey white, nodular infiltrating in hilum
Arising from major bronchus or trachea
Infiltrating into surrounding region
Spread to lymph nodes or extrapulmonary
Grey white, nodular- peripheral/hilar
Hx of Central scar, women, non smokers
Expanding tumour
Spread to lymph nodes or extrapulmonary
Markers
Neuroendocrine cells
ACTH, ADH, calcitonin
Epithelial cells
PTH-rp
EGFR
ALK
KRAS
Extra information
Paraneoplastic:
- Cushing’s (ACTH)
- ADH (low Na+, SIADH, diabetes insipidus
- Calcitonin: hypocalcemia
- Gastrin releasing peptide: peptic ulcer
- Myasthenic syndrome
- Hypercalcaemia
Haematologic syndromes:
- Migratory thrombophlebitis
- Non bacterial endocarditis
Prognosis/ treatment
Poor- early spread
Surgery not an option (chemotherapy and radiotherapy)
Rb mutations >90%
KRAS, EGFR, ALK negative
Better prognosis
Late spread
Early surgical resection
Rb mutations 20%
KRAS EGFR ALK often +
Better prognosis
Late spread
Early surgical resection
Rb mutations 20%
KRAS EGFR ALK often +
Other types of lung cancers:
Other types of lung cancers:
- Bronchiolo-alveolar carcinoma (adenocarcinoma in situ):
- Involves peripheral parts of the lung, as a single nodule
- Diameter of 3 cm or less; columnar cells grow along pre-existing structures (bronchioles and alveoli) with no destruction of alveolar architecture or stromal invasion
- May present with pneumonia-like consolidation on imaging; excellent prognosis
- Carcinoid tumour:
- Bronchial carcinoids occur at an early age (mean 40 years); represent 5% of all pulmonary neoplasms; no relation to smoking
- Malignant tumours composed of cells that contain neurosecretory granules in their cytoplasm
- Most originate in main bronchi and grow in one of two patterns: (1) an obstructing polypoid, spherical, intraluminal mass or (2) a mucosal plaque penetrating the bronchial wall to fan out in the peri-bronchial tissue
- Well demarcated; distant metastasis is rare
- Most manifest with signs and symptoms related to their intraluminal growth (cough, haemoptysis)
- Rarely may secrete hormonally active polypeptides, inducing the carcinoid syndrome (intermittent attacks of diarrhoea, flushing and cyanosis)
- Often resectable and curable
- Pleural tumours – mesothelioma:
- Rare cancer of mesothelial cells, usually arising in the parietal or visceral pleura
- Related to occupational exposure to asbestos in the air (approximately 50% of patients with this cancer have a history of asbestos exposure
- Latent period for developing malignant mesothelioma is long, often 25-40 years after initial asbestos exposure (suggests that multiple somatic genetic events are required for neoplastic conversion of a mesothelial cell)
- Often preceded by extensive pleural fibrosis and plaque formation; tumours begin in a localised area and over time spread widely
- The affected lung typically is ensheathed by a yellow-white, firm, sometimes gelatinous layer of tumour that obliterates the pleural space
- Distant metastases are rare
- Other tumours:
- Metastasis to lung:
- Most common sources are breast and colon carcinoma
- Multiple ‘cannon-ball’ nodules on imaging
- More common than primary tumours
- Lung hamartoma:
- Benign lung tumour; due to embryonic disorganisation
- Approximately 80% are found in the lung periphery
- Rounded or nodular
- Composed of normal tissue like cartilage, connective tissue, fat and muscle but in a haphazard arrangement
- Pancoast tumours:
- Apical neoplasm – may invade the brachial or cervical sympathetic plexus to cause severe pain in the distribution of the ulnar nerve or to produce Horner syndrome (ipsilateral enophthalmos, ptosis, miosis and anhidrosis)
- Accompanied by destruction of the first and second ribs and sometimes thoracic vertebrae
Anatomy of the lung and pleura – including blood supply & lymphatic drainage.
- Left lung has 2 lobes (upper and lower) divided by oblique fissure, smaller vs right due to heart
- Right lung is larger and has 3 lobes: upper and middle divided by horizontal fissure and middle and lower divided by the oblique fissure
- Pleura: parietal and visceral layers but continuous with each other – tiny amount of serous fluid separating the layers (prevent friction) – pleura allows for creation of negative pressure – allows for inspiration of air into lungs
- Hilum: major bronchi, pulmonary vessels, hilar LN
- Normal = left hilum higher than right
- Blood supply:
- Pulmonary trunk from RV (carrying deoxygenated blood) à bifurcates early into L + R pulmonary arteries à passes through each hilum and branches to supply L + R lung eventually terminating in pulmonary capillaries à O2 diffuses into pulmonary capillaries and CO2 diffuses out into alveolar space à blood travels back to heart oxygenated via 4x pulmonary veins
- pulmonary system is low pressure system (much lower vs systemic circuit)
- in response to low PaO2 blood vessels undergo hypoxic pulmonary vasoconstriction to promote blood flow to areas of the lung that are better ventilated (automatic mechanism for matching ventilation and perfusion)
- V/Q ratio highest at apex (high PO2, low PCO2), base of lung has lowest V/Q ratio (lower PaO2, higher PCO2) – regardless of this both ventilation and perfusion are better at the base of the lung
- Note: bronchial arteries carry oxygenated blood and branch from systemic circulation
- Left bronchial from thoracic aorta
- Right bronchial from posterior intercostal artery
- These bronchial arteries supply the pulmonary tissue and then empty into pulmonary veins and enter LA
- There are bronchial veins too but only a small proportion of blood supplied by bronchial arteries is returned by bronchial veins (mostly via pulmonary veins)
- Lymphatic drainage:
- Segmental and interlobar nodes of bronchiole and bronchi drain toward the hilus (there is a superficial and deep lymphatic plexus)* à drain to the pulmonary (intrapulmonary) nodes à bronchopulmonary nodes àinferior (carinal) and superior tracheobronchial nodes à the tracheal (paratracheal) nodes à bronchomediastinal nodes and trunks àeventually to the thoracic duct on the left and right lymphatic duct on the right.
- Superficial lymphatic plexus = subpleural
- Deep lymphatic plexus à accompanies bronchovascular structures with associated intrapulmonary LN
Number
Name
superior mediastinal
paratracheal
paratracheal/retrotracheal
lower paratracheal/azygous/tracheobronchial
subaortic
para-aortic
carinal/sub-carinal
paraoesophageal
pulmonary ligament (not a LN = parietal pleura folded)
hilar
intrapulmonic/interlobar
peribronchial
segmental
Note: in terms of “N” staging (TNM) of lung cancer
Note: in terms of “N” staging (TNM) of lung cancer
Pulmonary LN = 12, 11, 10, 13 = N1
Superior mediastinal LN = 1,2,3,4 = N2-3
Aortic LN = 5,6 = N2-3
Inferior mediastinal
- 7 = N2
- 8,9 = N2-3
Physiology of respiration, blood gases and lung function tests.
- Inspiration: use diaphragm and external intercostal muscles (active process)
- Diaphragm contracts down, external intercostals contract (ribs move out and up) à creates negative intrapulmonary pressure à air flows in to increase lung volume
- Expiration: passive, elastic recoil of lungs causes decreases lung volume, positive intrapulmonary pressure and air flows out
- Blood gases:
- Measure: PaO2, PaCO2, anion gap, bicarb, pH, H+, base excess
- PaO2 below 60mmHg (non-COPD patient) = respiratory failure (point at which O2 dissociation curve takes sharp decline – rapid unloading of oxygen)
- Type I vs type II resp failure
- Type I: PaO2 dec but PaCO2 normal or decreased
- Type II: PaO2 dec, PaCO2 increased
- Metabolic acidosis/alkalosis? Respiratory alkalosis/acidosis?
- Can be used to assess whether mechanical ventilation is necessary
Clinical assessment of lung function, arterial blood gas analysis.
Metabolic Alkalosis
Metabolic Alkalosis
Respiratory Acidosis
Respiratory Alkalosis
pH
↓
↑
↓
↑
PaCO2
N (uncompensated)
↓ (compensated)
N (uncompensated)
↑ (compensated)
↑
↓
HCO3ˉ
↓
↑
N (uncompensated)
↑ (compensated)
N (uncompensated)
↓ (compensated)
Base excess
↓
↑
N/↑
N/↓
Clinical features
Kussmaul-type breathing (deeper, faster respiration), shock, coma
Paraesthesia, tetany, weakness
Acute: air hunger, disorientation
Chronic: hypoventilation, hypoxia, cyanosis
Acute: hyperventilation, paraesthesia, light-headedness
Chronic: hyperventilation, latent tetany
Common causes
With raised anion gap: diabetic ketoacidosis, lactic acidosis, poisons (e.g. ethylene glycol), drug overdoses (paracetamol, aspirin, isoniazid, alcohol)
With normal anion gap: diarrhoea, secretory adenomas, ammonium chloride poisoning, interstitial nephritis
Vomiting, prolonged therapy with potassium-wasting diuretics or steroids, Cushing’s disease, ingestion/overdose of sodium bicarbonate (e.g. antacids)
Hypoventilation
chronic lung disease with CO2retention, e.g. chronic obstructive pulmonary disease, respiratory depression from drugs (e.g. opioids, sedatives), severe asthma, pulmonary oedema
Hyperventilation anxiety, pain, febrile illness, hypoxia, pulmonary embolism, pregnancy, sepsis
Clinical examination for lung disorders
- spirometry
- physical examination
- Flow volume tests
- Assessing acute response to bronchodilators
- Confirm or exclude asthma
- Specialist referral
- Exercising testing
- Sleep studies
- Chest x-ray
- High resolution CT
- Ventilation and perfusion scans
- Transcutaneous oxygen saturation
- Arterial blood gad measurements
- Sputum examination
- Haematology and biochemistry
- ECG and Echo
- Trials of therapy
- Optimise function
- Prevent deterioration
- Develop a care plan
- Manage exacerbations
Diagnosis of malignant hypertension.
A diagnosis of malignant hypertension is based on blood pressure readings and signs of acute organ damage. Order blood and urine tests that may include: Blood urea nitrogen (BUN) and creatinine levels, which increase if you have kidney damage.
Diagnosis of paraneoplastic syndromes – especially those associated with lung cancer.
PNS are detected before cancer is diagnosed in 80% of cases. … Depending on the affected nervous system compartment, PNS symptoms may include cognitive and personality changes, ataxia, cranial nerve deficits, weakness, or numbness. A full neurological examination is performed.
Imaging
Solitary pulmonary nodules:
- A solitary pulmonary nodule is radiologically defined as a nodule <3cm in diameter with no associated atelectasis or lymphadenopathy
- The lesion is likely to be benign if there has been no change in the size of the nodule after two years.
- Lesions that have the potential for malignancy require evaluation and follow-up
Image 2: There is a circumscribed mass arising from the right hilum with spotty calcification. Biopsy confirmed bronchial carcinoid tumour
Non small cell cancer (staging)
- Staging of NSCLC is important as stages I-III are potentially resectable and sometimes curable.
- Chest radiography is indicated in all patients but has a low sensitivity for detecting lesion spread
- CT is most useful in staging of NSCLC and is often combined with PET
Image 1a: Left hilar mass causing collapse of the left upper lobe and elevation of the left main bronchus
Image 1b, 1c and 1d: CT of the same patient reveals a large, relatively homogenous mass within the left upper lobe measuring 95mm and extending from the apex to the hilum. Central areas of low attenuation are compatible with tissue necrosis. There is also encasement of the left upper lobe bronchus and pulmonary artery with extensive background emphysema
Image 2a: Lobectomy showing large non-small cell lung carcinoma arising from the proximal bronchus and invading into the surrounding parenchyma. Note the patchy central necrosis and punctate areas of haemorrhage
Images 2b and 2c: Post-mortem specimens showing infiltration of lung parenchyma by bronchoalveolar carcinoma.
Staging of lung cancer and the likely prognosis.
Stage using CT. Common site such as liver, adrenal bone and brain need to be included. PET-CT has got a low PPV.
Outlining the likely course of events and interventions once the diagnosis has been made.
Who should investigate and manage this patient? How urgently? How is this arranged?
Assess fitness before radical treatment. Full lung function testing, if CVD is present, stress echo need to be done.
this arranged?
Surgery is performed at early stage of NSCLC (I, II, IIIa) with a curative intention. Patients with stage III can undergo intensive chemoradiation to downstage rendering it amenable to surgical resection.
Radiation therapy provide a comparable outcome to surgery and is the treatment of choice for patient not qualify for surgery due to other comorbidities.
The importance of providing continuity of primary care throughout this process.
Patients with lung cancer are often independent and pain free in comparison to other form of cancer but they die rapidly at terminal stage. Patient and family require emotional and psychological support. The palliative care team include the respiratory team, social workers, hospital chaplains, and the nurses.
Side effects of chemotherapy drugs.
Most common: Nausea, hairloss, tiredness, mucositis and myelosuppression. Side effects are much more dose dependent than the anti-cancer effect so it has been practice to give the highest dose patients can tolerate.
· All chemotherapy need to be administered by trained staff because leakage outside the vein will cause tissue necrosis so immediate local measure such as aspiration has to be instigated.
· Nausea and vomiting: A stepped wise antiemetics approach. Such as metoclopramide and domperidone followed by 5-HT3 antagonists with dexamethasone.
· Hairloss: Beau’s line – white line on nails reflecting the periods of cessation of growth. Skin toxicity pronounced with 5-FU.
· Fatigue: continue beyond completion of therapy. Compound with anemia or depression.
· Myelosuppressive: platelet, WBC and RBC. Can be managed by transfusion and prophylactic antimicrobials/G-CSF.
· Mucositis: mucosa is very sensitive. Can cause severe pain at oropharynx and life threatening diarrhea. Palifermin is a recombinant keratinocyte-derived growth factor.
