Respiratory Histopathology (Cancer)

Question 1

What are the characteristics of benign lung tumours?

Answer 1

Do not metastasise

Can cause local complications
Airway obstruction

E.g. chondroma

Question 2

What are the characteristics of malignant lung tumours?

Answer 2

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

Commonest are epithelial tumours, and of these main types (90-95%)

Question 3

What are the non small cell carcinomas and how much of total lung cancer burden do each of these make up?

Answer 3

Squamous cell carcinoma (30%)
Adenocarcinoma (30%)
Large cell carcinoma (20%)

Question 4

What % of the lung cancer burden does small cell lung cancer make up?

Answer 4

20%

Question 5

What are the common sites of lung cancer?

Answer 5

Left main bronchus
Bronchioles
Lung base
Pleura

Question 6

What is the epidemiology of lung cancer?

Answer 6

1 in 7 new cancer cases
Almost 40,000 cases lung cancer in 2007
Men:women 4:3, but increasing numbers of women (1960’s ratio 6:1)
Men – second commonest to prostate cancer
Women – third commonest after breast and bowel cancer
Global cancer

Question 7

What causes lung cancer?

Answer 7

Smoking - small cell and squamous cell

Question 8

What does smoke contain?

Answer 8

Tumour initiators: Polycyclic aromatic hydrocarbons
Tumour promotors: N Nitrosamines, Nicotine, Phenols
Complete carcinogens: Nickel, Arsenic

Question 9

25% of lung ca in non-smokers attributed to passive smoking

Answer 9

25% of lung ca in non-smokers attributed to passive smoking

Question 10

Does stopping cigarette smoking decrease you risk of lung cancer?

Answer 10

Yes

Question 11

What are non smoking risk factors of lung cancer?

Answer 11

Environment:

1. Asbestos exposure (Asbestos + smoking = 50 fold increase risk)
2. Radiation (Radon exposure, theraputic radiation, uranium miners)
3. Air pollution
4. Other: Heavy metals (Chromates, arsenic, nickel)

Genetics: Familial lung cancers rare, 1st degree relative (young age, non-smoking cases), Susceptibility genes

Question 12

Which susceptibility genes exist for lung cancer?

Answer 12

Chemical modification of carcinogens
Polymorphisms in genes for cytochrome p450 (CYP1A1) and glutathione S transferases which play a role in eliminating carcinogens
Susceptibility to chromosome breaks and DNA damage
Nicotine addiction

Question 13

How does lung cancer develop?

Answer 13

Multistep pathways:
metaplasia, dysplasia, carcinoma-in-situ to invasive carcinoma.

Associated with accumulation of gene mutations leading to disordered unregulated growth, tissue invasion, angiogenesis

Pathways different for different tumour types

For some lung tumours a precursor lesion is not identifiable e.g. small cell carcinoma

Question 14

Which Mutation confers the most risk of SCC?

Answer 14

Gene methylation (p16ink4)

3pLOH, microsatellite alterations (50-80% of SCC)

Question 15

Summarise Invasive Squamous Cell Carcinoma

Answer 15

Frequency
35% pulmonary carcinoma

Risk factor
Closely associated with smoking

Site
Traditionally centrally located arising from bronchial epithelium, however increasing number of peripheral squamous cell carcinomas

Behaviour
Local spread, metastasise late.

Question 16

What is the precursor lesion to Adenocarcinoma (AC)

Answer 16

Precursor lesion: Atypical adenomatous hyperplasia
Proliferation of atypical cells lining the alveolar walls.
Increases in size and eventually can become invasive.

Question 17

How does AAH progress to AC?

Answer 17

AAH
Non mucinous BAC
Mixed pattern adrenocarcinoma

Question 18

What are the molecular pathways to adenocarcinoma?

Answer 18

Stem cells identified in TRU mice
in mice with kras mutation - serial changes from aah to bac to 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?

Question 19

How frequent is an invasive adenocarcinoma?

Answer 19

Increasing incidence: 27% pulmonary carcinomas

Question 20

What are the risk factors for an invasive adenocarcinoma?

Answer 20

Smoking + other

Commoner in far east, females and non-smokers

Question 21

What is the site and behaviour of an invasive adenocarcinoma?

Answer 21

Site
Peripheral and more often multicentric

Behaviour
Extrathoracic metastases common and early (80% present with mets)

Question 22

What is the histology of an invasive adenocarcinoma?

Answer 22

Histology shows evidence of glandular differentiation

Question 23

What is a large cell carcinoma?

Answer 23

Peripheral or central 10% of tumours

Poorly differentiated tumours composed of large cells

No histological evidence of glandular or squamous differentiation

Poorer prognosis

Question 24

What does electron microscopy of a large cell carcinoma show?

Answer 24

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

Question 25

When and where are small cell carcinomas?

Answer 25

When: 20% of tumours, smokers Where: Near bronchi (central)

Question 26

How do small cell carcinomas act?

Answer 26

80% present with advanced disease Although very chemosensitive, have an abysmal prognosis Paraneoplastic syndromes Small poorly differentiated cells p53 and RB1 mutations common

Question 27

Which non small cell lung cancer currently has the highest incidence?

Answer 27

Adenocarcinoma

Question 28

How is survival different between small cell and non small cell lung cancers?

Answer 28

SC: Survival 2-4 months untreated, 10-20 months with current therapy NSC: Early Stage 1: 60% 5 yr survival Late Stage 4: 5% 5 yr survival

Question 29

Which type of lung cancer is more chemosensitive?

Answer 29

Small cell lung cancer

Question 30

Which NSCLC are important to differentiate for treatment?

Answer 30

Particularly : Adenocarcinoma vs squamous cell carcinoma Some adenocarcinomas show a variety molecular changes which can be targeted by specific therapies. EFGR mutation ALK translocation Ros1 translocation In contrast some patients with squamous cell carcinoma develop fatal haemorrhage with some new chemotherapeutic drugs (Bevacizumab)

Question 31

What can you look at in cytology?

Answer 31

``` Cytology - looking at cells Sputum Bronchial washings and brushings Pleural fluid Endoscopic fine needle aspiration of tumour/enlarged lymph nodes ```

Question 32

What can you look at in histology?

Answer 32

Histology - looking at tissue Biopsy at bronchoscopy - central tumours Percutaneous CT guided biopsy - peripheral tumours Mediastinoscopy and lymph node biopsy - for staging Open biopsy at time of surgery if lesion not accessible otherwise - frozen section Resection specimen - confirm excision and staging

Question 33

What treatment pathway aims to be curative?

Answer 33

Curative: Surgery +/- radical chemoradiotherapy +/- immunemodulatory therapy

Question 34

Which treatment pathway aims to be palliative?

Answer 34

Palliative: Chemoradiotherapy, immunemodulatory, targeted therapy

Question 35

What do you look for in molecular testing?

Answer 35

EGFR mutation Responder mutation Resistance mutation Alk translocation Ros1 translocation

Question 36

What are the types of molecular testing?

Answer 36

ALK, immunohistochemistry and FISH

Question 37

What is a mesothelioma?

Answer 37

Malignant tumour of pleura (lining of the lung and chest wall)

Question 38

Summarise a malignant mesothelioma

Answer 38

Frequency <1% of cancer deaths, but increasing incidence ? Peak in incidence in about 2010. Aetiology asbestos exposure Behaviour Essentially a fatal disease Medicolegal implications of diagnosis compensation

Question 39

Who gets mesothelioma?

Answer 39

Most patients have history of asbestos exposure Long lag time: Tumour develops decades after exposure males>females, approx 3:1 50-70 years of age Present with shortness of breath, chest pain Dismal prognosis

Question 40

What can help in ALK translocation in cancers?

Answer 40

Crizotinib

Question 41

What can be used to treat lung cancer?

Answer 41

mAbs | Immunotherapy

Question 42

What % of lung cancers in the UK develop in non smokers?

Answer 42

10-20%

Question 43

Stopping at any point reduces risk of lung cancer

Answer 43

Stopping at any point reduces risk of lung cancer