Pathology of lung cancer Flashcards
How can we stage a tumour
Clinically, radiologically and pathologically
Summarise the anatomy of the airways
Airway conductive system
Gas exchange compartment
Airways
Alveolar parenchyma
Epithelium
Interstitium
Vasculature
Arteries
Veins
Lymphatics
Pleura
Describe the branching of the tubular system
Asymmetrical dichotomous branching tubular system
(up to) 24 divisions
Bronchi > ~ 1mm
Bronchioli < 1mm
“Small airways” < 2mm
Gets harder to sample as you go down- why you need CT to guide
Summarise airway histology
surfaced by ciliated epithelium to waft mucous with trapped particles, smoke and bacteria; supported by cartilage to stop collapsing under pressure - lost in periphery airways
loss of cartilage in bronchioles and alveoli- but ciliated epithelium still present
Where can lung cancer arise
Lung cancer location: can arise in large airways, terminal airways or within alveoli themselves
Why does lung cancer arise
SMOKING (at least 75% attributable, ? 25% of non-smokers attributed to passive smoking)
Tumour initiators, promotors and complete carcinogens
Polycyclic aromatic hydrocarbons
Phenols
Nickel, Arsenic
Lung cancer in NON-smokers
Asbestos exposure (Asbestos + smoking = 50 fold increase risk)
Radiation (Radon exposure- higher in certain areas, therapeutic radiation)
Genetic predisposition
Familial lung cancers rare
Other: Heavy metals (Chromates, arsenic, nickel)
Summarise the development of carcinoma
Multistep accumulation of mutations resulting in:
Disordered growth
Loss of cell adhesion
Invasion of tissue by tumour
Stimulation of new vessel formation around tumours
Mutations occur in epithelial cells and stem cells.
Pathways different for different tumour types- key to their molecular pathogenesis and phenotype- implications for targeted therapy
Reflected in histology of tumours
What is key to remember about the pathogenesis of carcinoma
It can be reversible- particularly the early stages
Summarise the cells that tumours can arise from
Tumours arise from a variety of cell types: Epithelial, mesenchymal (soft tissue), lymphoid
Describe benign tumours
Do not metastasise
Can cause local complications
Airway obstruction
E.g. chondroma
Describe malignant tumours
Potential to metastasise, but variable clinical behaviour from relatively indolent to aggressive
Commonest are epithelial tumours : “carcinomas”
Describe the common epithelial malignant lung cancers
“Non-small cell carcinoma”
Squamous cell carcinoma 20-40%
Adenocarcinoma 20-40%
Large cell carcinoma - uncommon
Small cell carcinoma 20%
Poorly differentiated, advanced, treat with radiotherapy- but relapse quickly
Describe the pathogenesis of squamous cell carcinoma
carcinoma of tough epithelium that usually lines skin; normal ciliated epithelium becomes irritated by smoke and undergoes metaplasia to become squamous cell epithelia without cilia - more resistant to damage but no cilia to move mucous; dysplasia and disordered growth occurs as mutations are accumulated and becomes carcinoma in situ
once dysplastic changes occur and it becomes carcinoma in situ- expresses growth factors and enzymes- allowing it then to invade the underlying tissue
List some of the mutations involved in the pathogenesis of carcinoma in situ
3pLOH, microsatellite alterations Myc overexpression and telomerase dysregulation Neoangiogenesis Gene methylation (p16ink4 K-ras mutation
Describe the characteristics of squamous cell carcinoma
25-40% pulmonary carcinoma
Closely associated with smoking
Traditionally central arising from bronchial epithelium, but recently increase in peripheral SqCC
Local spread, metastasise late.
Why do we now see squamous cell carcinoma in the peripheries too
Due to low tar cigarettes- carcinogens can penetrate further down the lungs
What is adenocarcinoma a tumour of
glandular epithelium
develops in interstitium and peripheral airways
Describe the precursor stage for adenocarcinomas
Atypical adenomatous hyperplasia - proliferation of atypical cells
Lining the alveolar walls. Increases in size and eventually can become
Invasive.
Don’t necessarily become invasive can stop growing and form a fibrous scar which will show on the CT
Describe the progression of atypical adenomatous hyperplasia
proliferation of atypical cells along alveolar walls; increase in size and eventually become invasive; adenocarcinoma-in-situ acquire invasive phenotype before invading local tissue and stroma - if can excise early lesions then will cure patient
Summarise the molecular pathways in adenocarcinoma
Precursor is type 2 pneumocyte or clara cell Smokers: K ras mutation DNA methylation p53
Non-smokers
EGFR mutation/
amplification
Mutually exclusive- if you have one mutation- won’t have the other
Describe the other molecular pathways involved in the development of adenocarcinoma
Other pathways TRU - non ras non EGFR (motoi 0/7 egfr, 2/7 ras)
Other pathways - mucinous BAC from bronchial mucus cells, CCAM
BCD?
Describe the histology of adenocarcinoma
Increasing incidence
25-40% pulmonary carcinomas
Commoner in far east, females and non-smokers
Peripheral and more often multicentric- more carcinogens- more areas of lung affected now
Extrathoracic metastases common and early
Histology shows evidence of glandular differentiation
Describe large cell carcinomas
Poorly differentiated tumours composed of large cells
No histological evidence of glandular or squamous differentiation
BUT on electron microscopy many show some evidence of glandular, squamous or neuroendocrine differentiation
i.e are probably very poorly differentiated adeno/squamous cell carcinomas
Poorer prognosis
Summarise small cell carcinomas
20-25% tumours
Often central near bronchi
Very close association with smoking
80% present with advanced disease
Although very chemosensitive, have an abysmal prognosis- within 18 months
Paraneoplastic syndromes
Chemosensitive as they have a rapid turnover- but not all cells affected- so relapse common
Describe the histology of small cell carcinomas
Small cells
Bags of chromatin- rapidly dividing- large number of mitoses- outgrow blood supply- so necrotic core common
Compare small cell lung tumours to non-small cell lung tumours
Small cell lung carcinoma
Survival 2-4 months untreated
10-20 months with current therapy
chemoradiotherapy (surgery very rarely undertaken as most have spread at time of diagnosis)
Non small cell lung carcinoma Early Stage 1: 60% 5 yr survival Late Stage 4: 5% 5 yr survival 20-30% have early stage tumours suitable for surgical resection. Less chemosensitive
Why are Advances in lung cancer treatment mean subtyping Non-small cell carcinoma important
Some patients with squamous cell carcinoma develop fatal haemorrhage with anti-angiogenic therapy Bevacizumab
Some chemo works better in adenocarcinoma – Pemetrexed
Variety of molecular abnormalities provide targets for treatment only found in adenocarcinomas
EGFR, ALK, ros, ret mutations
Where are most molecular targets found
Adenocarcinomas
Describe EGFR
Membrane receptor tyrosine kinase
Regulates angiogenesis, proliferation, apoptosis and migration
Mutation/amplification in NSCLC
Non-smokers, females, asian ethnicity
Adeno 46% vs Squam 5%
Target of tyrosine kinase inhibitor (TKI)- can target various sites in the molecular pathway
What is EGFR inversely related with
Inverse correlation with presence of kras mutation
75% of studies found not prognostic
Describe the importance of tyrosine kinase inhibitors
Tyrosine kinase inhibitors stop downstream processes and increase survival time
Describe ALK
Similar striking responses reported with other TKIs
ALK – non-smoker, adc, signet ring sub-type, young male
Screen for alk using IHC – good concordance with FISH results
Dramatic response to TKI
Gene rearrangement
Summarise immunomodulatory therapy
Long been recognised that there is a host immune reaction to tumours – see it under the microscope and in some tumours can be predictive better outcome
Complex interaction between tumour cells, immune cells and other host cells
Ongoing battle as host immune system tries to target cancer cells and cancer cells try to evade immune system
PDL- expressed by adenocarcinomas is PDL-1- blocks action of cytotoxic T lymphocytes-
can give PDL-1 inhibitors
Can see a significant and sustained response of PDL1 positive tumours to PDL1 inhibitor
Again – tumours may not show complete response and can develop resistance to PDL1 inhibitor
Describe cytology
Sputum
Bronchial washings and brushings
Pleural fluid
Endoscopic fine needle aspiration of tumour/enlarged lymph nodes
Describe histology
Biopsy
Central tumour - bronchoscopy
Peripheral tumours – CT guided biopsy through skin
Surgical biopsy :
Mediastinal lymph node biopsy - for staging
Open biopsy at time of surgery if lesion not accessible otherwise – “frozen section”
Ultimate “biopsy” Resection specimen - confirm excision and staging
Why may a surgical biopsy be necessary
If tissue hard to biopsy (behind scapula)- remove- diagnose type an can be done during operation to see if malignant within 15 minutes d stage
Summarise TNM staging
T TUMOUR (T1-4) Size, Invasion pleura, invasion other structures e.g. pericardium
N LYMPH NODE METASTASIS (N0-3)
N0 – lymph node not involved by tumour
N1 or N2 or N3 - lymph nodes involved by tumour
M DISTANT METASTASIS (M0 or 1)
M1 – tumour has spread to distant sites
E.g. tumour in liver, bones, brain (includes separate tumour nodule in different lobe of lung)
It is a measure of how advanced a tumour is:
Each patient given T N and M stage and together these give information about prognosis and operability.
Can be clinical, radiological or pathological (the latter is most accurate)
What is the most accurate staging technique
Pathological
Radiological- may appear larger due to inflammation- same with nodal- node may look big- but may just be inflammation- pathological is therefore the most accurate
Describe bronchial obstruction
- Bronchial obstruction
Collapse of distal lung
Shortness of breath
Impaired drainage of bronchus
Chest infection
Pneumonia, abscess
Describe the invasion of local structures
Invasion of local airways and vessels Haemoptysis, cough Invasion around large vessels Superior vena cava syndrome- venous congestion of head and arm oedema and ultimately circulatory collapse Oesophagus Dysphagia Chest wall Pain Nerves Horners syndrome
Describe Inflammation/irritation/ invasion of pleura or pericardium
Pleuritis or pericarditis, with effusions
Breathlessness
Cardiac compromise
Describe the systemic effects of bronchogenic carcinoma
Physical effects of distant spread brain (fits) skin (lumps) liver (liver pain, deranged LFTs) bones (bone pain, fracture)
Paraneoplastic Syndromes: Systemic effect of tumour due to abnormal expression by tumour cells of factors (e.g. hormones and other factors) not normally expressed by the tissue from which the tumour arose
Endocrine e.g. “Syndrome of inappropriate antidiuretic hormone” causing hyponatremia (especially small cell carcinoma)
Non-endocrine e.g. Haematologic/coagulation defects
What is meant by paraneoplastic syndrome and give examples
Paraneoplastic syndrome: syndrome of signs and symptoms that are not due to the local presence of cancer cells, rather are a response to humoral factors such as hormones/cytokines secreted by the tumours or as part of an immune response
Examples:
Small cell lung cancers may secrete ectopic ACTH causing Cushing’s, or ADH leading to water retention
Squamous cell carcinomas may secrete PTH causing hypercalcaemia
Lung cancers may have various neurological conditions associated with autoimmune reactions or immunological responses
Give some endocrine and non-endrocrine causes of paraneoplastic syndrome
- Antidiuretic hormone (ADH)
“Syndrome of inappropriate antidiuretic hormone” causing hyponatremia (especially small cell carcinoma) - Adrenocorticotropic hormone (ACTH)
Cushing’s syndrome (especially small cell carcinoma) - Parathyroid hormone-related peptides
Hypercalcaemia (especially squamous carcinoma)
NON-endocrine
Haematologic/coagulation defects, skin, muscular, miscellaneous disorders
Describe mesothelioma
Mesothelioma risk factors: asbestos exposure is the main risk factor, with increasing exposure linked to increased risk (some genetic component exists too)
Pathology: mesothelium is a layer of cuboidal epithelial cells lining the pleural cavity, and deposition of asbestos fibres in the lung parenchyma can cause penetration of the visceral pleura and development of plaques and tumour development
