Mark james Flashcards
lung cancer
What are the 3 subtypes of NSCLC?
(i) Squamous cell carcinoma (25%)- central
(ii) Adenocarcinoma (40%)- peripheral
(iii) Large cell carcinoma (10%) - either
Give 5 histological features of SCC of the lung (KIMND)
(1) Keratinization with keratin pearls
(2) Intercellular bridges
(3) High nuclear to cytoplasmic ratio
(4) Increased mitotic figures
(5) Desmoplastic stroma surrounding the tumour
Give 5 histological features of adenocarcinoma of the lung
(1) Glandular differentiation
(2) Acinar or papillary pattern
(3) Presence of mucin within cells
(4) Desmoplastic stroma
(5) increased mitotic figures
list the 3 pre-cursor lesions for lung carcinomas
(1) Squamous cell dysplasia / carcinoma in situ -> SCC
(2) Atypical adenomatous hyperplasia/ adenocarcinoma in situ -> Adenocarcinoma
(3) Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia -> SCLC
Carcinomas arise from what cells?
Epithelial cells (derived from all 3 germ layers, endoderm, mesoderm and ectoderm)
list the 4 stages of malignant cell spread
(1) loosening on inter-cellular connections (E-cadherin) due to mutational inactivation or suppression of E-cadherin genes
(2) Degradation of BM and interstitial connective tissue
–> Proteolytic enzymes (MMP’s, Type IV collagenase, urokinase plasminogen activator, cathepsin D)
(3) Detachment of cell from BM (loss of polarity)
(4) Locomotion through BM and ECM
-> autocrine motility factors enhance and direct movement of cells
-> Insulin-like growth factors attract tumour cells
describe 4 reasons why cancer cells commonly metastasize to bone
(1) Chemokine/cytokines
-> Cancer cells can be “homed” to bone tissue due to expression of certain receptors which are attracted to chemokines released from bone cells. Example: Cancer cells expressing CXCr4 can be homed to bones through chemokine CXCL2 release.
(2) Factors released from bone
-> TGF-B, PDGF and IGF released from the bone can promote cancer cell growth and proliferation making the bone microenvironment conducive for tumour growth.
(3) Modulation of immune response.
- Cancer cells can suppress cytotoxic T-cell activity and upregulate T-regulatory cell activity. This creates an immunosuppressed environment which facilitates tumour growth.
(4) Bone remodelling
- regular bone remodelling can allow for tumour cells to lodge in the boney matrix.
-This can be enhanced by upregulation of osteoclast activity by tumour cells which can create lytic lesions allowing for further invasion into the bone.
What is atelectasis, what are the different types?
Atelectasis is the collapse of alveoli within the lung
(1) Obstructive atelectasis, also called resorptive atelectasis, occurs when there is obstruction to airflow to the alveoli (mucous plug, tumour, foreign body). The trapped air in the alveoli eventually gets resorbed into the pulmonary circulation causing alveolus collapse.
(2) Non-obstructive atelectasis
-Adhesive atelectasis: caused by surfactant deficiency which results in increased surface tension and alveolar collapse. Often caused by general anaethesia use as this reduces surfactant.
- Compression atelectasis: caused by compression of the lungs from pleural effusion, tumour, diaphragmatic hernia which causes alveolar collapse.
- Contraction atelectasis: caused by fibrosis and scarring of the lungs which causes collapse: seen in TB and sarcoidosis.
Most common cause is post-surgery and general anaesthesia which reduces surfactant and alveolar volume.
based on light’s criteria, what suggests an exudative pleural effusion
(1) Protein:
-Pleural fluid protein vs serum protein ratio > 0.5
(2) LDH
-Pleural fluid LDH vs serum LDH > 0.6
-Pleural LDH is > 2/3rds the upper limit of normal serum LDH levels.
Additionally
-Low glucose (<60mg/dL) in exudative effusions
-Pleural fluid cholesterol vs serum cholesterol ratio >0.3 or > 55mg/dL
4 signs of effusion on CXR
(1) Blunting of costophrenic angles
(2) Opacification of lungs (if large effusion)
(3) Meniscus sign due to fluid accumulation at base of lungs.
(4) Tracheal deviation away from effusion if large
(5) loss of visualisation of heart contour and hemidiaphragm if severe
What suggests effusion on ultrasound?
Hypo-echoic or anechoic (dark) collection in the costo-diaphragmatic recess.
Classify pneumothorax with causes of each
(1) Spontaneous pneumothorax
-Primary: no underlying disease - seen in young, tall, thin men/ rupture of bullae on lung surface
-secondary: underlying lung disease - CF, TB, COPD, lung cancer
(2) Iatrogenic
-Thoracentesis, central venous catheter placement, lung biopsy, mechanical ventilation
(3) Traumatic
- direct chest wall injury
(4) Tension
- Medical emergency whereby creation of one-way valve allows for air to enter pleural space with each inspiration but cannot escape - pleural pressure increases and compresses lung, heart and major vessels, impairs venous return-> cardiac arrest
describe the pathophysiology of finger clubbing
(1) Right to left shunts or pulmonary disease allows for megakaryocytes to enter systemic circulation. These are generally broken down in pulmonary capillary beds. These cells lodge in nail beds and release platelet-derived growth factor (PDGF) and VEGF which causes connective tissue hypertrophy and increased capillary permeability.
(2) Secretion of growth factors (e.g., platelet-derived growth factor and hepatocyte growth factor) from the lungs.
(3) Overproduction of prostaglandin E2 by other tissues
list 4 paraneoplastic syndrome associated with lung cancer and for each indicate the cancer subtype it is most associated with
Neuromuscular SCLC
-Lambert Eatson Myasthenic Syndrome: Antibodies produced against the pre-synaptic VG calcium channels of cholinergic neurons. This causes reduced Ach release - proximal muscle weakness, reduced or absent tendon reflexes, dry mouth, visual disturbance
Neurological SCLC
-Limbic encephalitis: Antibodies produced against brain tissue, particularly that of the limbic region. Associated withAnti-Hu antibodies.
Endocrine
-Hypercalcemia (SCC) - PTHrP production
-Cushings (SCLC) - ACTH production
-SIADH (SCLC) - ADH production
Integumentary
-Acanthosis nigricans (adenocarcinoma) : tumour secretion of growth factors such as TGF-a –> darkened skin patches in skin folds
Skeletal
- Hypertrophic pulmonary osteoarthropathy: NSCLC : Clubbing + Periostitis -> Megakaryocytes accumulate in distal vessels of the phalanges and release growth factors such as PDGF and VEGF -> fibrovascular proliferation
Explain how immune checkpoint inhibitors work in cancer treatment
PD-1 inhibitors (pembrolizumab)
PDL-1 inhibitors (atezolizumab)
CTLA-4 inhibitors (ipilimumab)
Checkpoints act to mediate and dampen down T cell activity in the body. This normally functions to prevent inappropriate and over-reactivity of cytotoxic T cells towards normal tissues, but also prevents T cells from recognising and attacking cancer cells.
PD1 and PDL-1 inhibitors
PDL-1 (on tumour cell) binds to PD1 (on T cell) to activate this immune checkpoint and effectively put a brake on the T cells response towards the cancer cell. This means the T cell does not attack and kill the cancer cell.
Therefore by blocking and inhibiting either of these receptors with a monoclonal antibody means that the checkpoint is not activated and the T cells response against the cancer cell is upregulated.
CTLA-4 inhibitors
CTLA-4 on T cells is normally bound by CD80/86 on an APC, again to dampen down and mediate T cells cytotoxic effects in the body. This again that prevent T cells from recognising cancer cells.
Therefore blocking CTLA4 on the T cell prevents this checkpoint from happening.
