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Respiratory System > Pathology of lung cancer > Flashcards

Pathology of lung cancer Flashcards

1
Q

How can we stage a tumour

A

Clinically, radiologically and pathologically

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2
Q

Summarise the anatomy of the airways

A

Airway conductive system
Gas exchange compartment

Airways

Alveolar parenchyma
Epithelium
Interstitium

Vasculature
Arteries
Veins
Lymphatics

Pleura

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3
Q

Describe the branching of the tubular system

A

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

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4
Q

Summarise airway histology

A

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

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5
Q

Where can lung cancer arise

A

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

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6
Q

Why does lung cancer arise

A

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)

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7
Q

Summarise the development of carcinoma

A

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

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8
Q

What is key to remember about the pathogenesis of carcinoma

A

It can be reversible- particularly the early stages

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9
Q

Summarise the cells that tumours can arise from

A

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

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10
Q

Describe benign tumours

A

Do not metastasise

Can cause local complications
Airway obstruction

E.g. chondroma

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11
Q

Describe malignant tumours

A

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

Commonest are epithelial tumours : “carcinomas”

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12
Q

Describe the common epithelial malignant lung cancers

A

“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

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13
Q

Describe the pathogenesis of squamous cell carcinoma

A

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

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14
Q

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

A 
3pLOH, microsatellite alterations
Myc overexpression and telomerase dysregulation
Neoangiogenesis
Gene methylation (p16ink4
K-ras mutation
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15
Q

Describe the characteristics of squamous cell carcinoma

A

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

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16
Q

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

A

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

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17
Q

What is adenocarcinoma a tumour of

A

glandular epithelium

develops in interstitium and peripheral airways

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18
Q

Describe the precursor stage for adenocarcinomas

A

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

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19
Q

Describe the progression of atypical adenomatous hyperplasia

A

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

20
Q

Summarise the molecular pathways in adenocarcinoma

A 
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

21
Q

Describe the other molecular pathways involved in the development of adenocarcinoma

A

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

22
Q

Describe the histology of adenocarcinoma

A

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

23
Q

Describe large cell carcinomas

A

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

24
Q

Summarise small cell carcinomas

A

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

25
Q

Describe the histology of small cell carcinomas

A

Small cells

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

26
Q

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

A

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
27
Q

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

A

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

28
Q

Where are most molecular targets found

A

Adenocarcinomas

29
Q

Describe EGFR

A

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

30
Q

What is EGFR inversely related with

A

Inverse correlation with presence of kras mutation

75% of studies found not prognostic

31
Q

Describe the importance of tyrosine kinase inhibitors

A

Tyrosine kinase inhibitors stop downstream processes and increase survival time

32
Q

Describe ALK

A

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

33
Q

Summarise immunomodulatory therapy

A

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

34
Q

Describe cytology

A

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

35
Q

Describe histology

A

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

36
Q

Why may a surgical biopsy be necessary

A

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

37
Q

Summarise TNM staging

A 
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)

38
Q

What is the most accurate staging technique

A

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

39
Q

Describe bronchial obstruction

A
  1. Bronchial obstruction
    Collapse of distal lung
    Shortness of breath

Impaired drainage of bronchus
Chest infection
Pneumonia, abscess

40
Q

Describe the invasion of local structures

A 
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
41
Q

Describe Inflammation/irritation/ invasion of pleura or pericardium

A

Pleuritis or pericarditis, with effusions
Breathlessness
Cardiac compromise

42
Q

Describe the systemic effects of bronchogenic carcinoma

A 
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

43
Q

What is meant by paraneoplastic syndrome and give examples

A

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

44
Q

Give some endocrine and non-endrocrine causes of paraneoplastic syndrome

A
  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

45
Q

Describe mesothelioma

A

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

Respiratory System (23 decks)

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