Pathology of lung cancer

Question 1

How can we stage a tumour

Answer 1

Clinically, radiologically and pathologically

Question 2

Summarise the anatomy of the airways

Answer 2

Airway conductive system
Gas exchange compartment

Airways

Alveolar parenchyma
Epithelium
Interstitium

Vasculature
Arteries
Veins
Lymphatics

Pleura

Question 3

Describe the branching of the tubular system

Answer 3

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

Question 4

Summarise airway histology

Answer 4

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

Question 5

Where can lung cancer arise

Answer 5

Lung cancer location: can arise in large airways, terminal airways or within alveoli themselves

Question 6

Why does lung cancer arise

Answer 6

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)

Question 7

Summarise the development of carcinoma

Answer 7

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

Question 8

What is key to remember about the pathogenesis of carcinoma

Answer 8

It can be reversible- particularly the early stages

Question 9

Summarise the cells that tumours can arise from

Answer 9

Tumours arise from a variety of cell types: Epithelial, mesenchymal (soft tissue), lymphoid

Question 10

Describe benign tumours

Answer 10

Do not metastasise

Can cause local complications
Airway obstruction

E.g. chondroma

Question 11

Describe malignant tumours

Answer 11

Potential to metastasise, but variable clinical behaviour from relatively indolent to aggressive

Commonest are epithelial tumours : “carcinomas”

Question 12

Describe the common epithelial malignant lung cancers

Answer 12

“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

Question 13

Describe the pathogenesis of squamous cell carcinoma

Answer 13

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

Question 14

List some of the mutations involved in the pathogenesis of carcinoma in situ

Answer 14

3pLOH, microsatellite alterations
Myc overexpression and telomerase dysregulation
Neoangiogenesis
Gene methylation (p16ink4
K-ras mutation

Question 15

Describe the characteristics of squamous cell carcinoma

Answer 15

25-40% pulmonary carcinoma
Closely associated with smoking
Traditionally central arising from bronchial epithelium, but recently increase in peripheral SqCC
Local spread, metastasise late.

Question 16

Why do we now see squamous cell carcinoma in the peripheries too

Answer 16

Due to low tar cigarettes- carcinogens can penetrate further down the lungs

Question 17

What is adenocarcinoma a tumour of

Answer 17

glandular epithelium

develops in interstitium and peripheral airways

Question 18

Describe the precursor stage for adenocarcinomas

Answer 18

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

Question 19

Describe the progression of atypical adenomatous hyperplasia

Answer 19

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

Question 20

Summarise the molecular pathways in adenocarcinoma

Answer 20

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

Question 21

Describe the other molecular pathways involved in the development of adenocarcinoma

Answer 21

Other pathways TRU - non ras non EGFR (motoi 0/7 egfr, 2/7 ras)
Other pathways - mucinous BAC from bronchial mucus cells, CCAM
BCD?

Question 22

Describe the histology of adenocarcinoma

Answer 22

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

Question 23

Describe large cell carcinomas

Answer 23

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

Question 24

Summarise small cell carcinomas

Answer 24

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

Question 25

Describe the histology of small cell carcinomas

Answer 25

Small cells | Bags of chromatin- rapidly dividing- large number of mitoses- outgrow blood supply- so necrotic core common

Question 26

Compare small cell lung tumours to non-small cell lung tumours

Answer 26

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 ```

Question 27

Why are Advances in lung cancer treatment mean subtyping Non-small cell carcinoma important

Answer 27

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

Question 28

Where are most molecular targets found

Answer 28

Adenocarcinomas

Question 29

Describe EGFR

Answer 29

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

Question 30

What is EGFR inversely related with

Answer 30

Inverse correlation with presence of kras mutation | 75% of studies found not prognostic

Question 31

Describe the importance of tyrosine kinase inhibitors

Answer 31

Tyrosine kinase inhibitors stop downstream processes and increase survival time

Question 32

Describe ALK

Answer 32

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

Question 33

Summarise immunomodulatory therapy

Answer 33

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

Question 34

Describe cytology

Answer 34

Sputum Bronchial washings and brushings Pleural fluid Endoscopic fine needle aspiration of tumour/enlarged lymph nodes

Question 35

Describe histology

Answer 35

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

Question 36

Why may a surgical biopsy be necessary

Answer 36

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

Question 37

Summarise TNM staging

Answer 37

``` 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)

Question 38

What is the most accurate staging technique

Answer 38

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

Question 39

Describe bronchial obstruction

Answer 39

1. Bronchial obstruction Collapse of distal lung Shortness of breath Impaired drainage of bronchus Chest infection Pneumonia, abscess

Question 40

Describe the invasion of local structures

Answer 40

``` 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 ```

Question 41

Describe Inflammation/irritation/ invasion of pleura or pericardium

Answer 41

Pleuritis or pericarditis, with effusions Breathlessness Cardiac compromise

Question 42

Describe the systemic effects of bronchogenic carcinoma

Answer 42

``` 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

Question 43

What is meant by paraneoplastic syndrome and give examples

Answer 43

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

Question 44

Give some endocrine and non-endrocrine causes of paraneoplastic syndrome

Answer 44

1. Antidiuretic hormone (ADH) “Syndrome of inappropriate antidiuretic hormone” causing hyponatremia (especially small cell carcinoma) 2. Adrenocorticotropic hormone (ACTH) Cushing’s syndrome (especially small cell carcinoma) 3. Parathyroid hormone-related peptides Hypercalcaemia (especially squamous carcinoma) NON-endocrine Haematologic/coagulation defects, skin, muscular, miscellaneous disorders

Question 45

Describe mesothelioma

Answer 45

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