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Clinical Pathology in Action > Lung Pathology > Flashcards

Lung Pathology Flashcards

1
Q

What is the epidemiology of lung cancer

A
  • Mone of the most common malignancies
  • Accounts for 1/3 of all cancer deaths in males
  • Occurs most often between the ages of 55 and 84 years
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2
Q

What are the classifications of lung cancer

A

In-situ carcinoma
- Adenocarcinoma
- Squamous Cell carcinoma

Invasive carcinoma

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3
Q

What types of invasive carcinomas are there in the lungs

A
  • Squamous cell carcinoma
  • Adenocarcinoma
  • Large cell undifferentiated carcinoma
  • Adeno-squamous carcinoma
  • Sarcomatoid carcinoma
  • Neuroendocrine tumours
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4
Q

What kind of neuroendocrine tumours are there

A
  • Carcinoid
  • Atypical carcinoid
  • Small cell carcinoid
  • Large cell neuroendocrine carcinoma
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5
Q

What are the risk factors of lung cancer

A
  • Smoking
  • Asbestos exposure
  • Radiation
  • Molecular genetics
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6
Q

How does cigarette smoking increase the risk of lung cancer

A

More than 1200 substances have been counted in cigarette smoke and many of these are potential carcinogens

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7
Q

What are the potential carcinogens in cigarette smoke

A
  • Polycyclic aromatic hydrocarbons
  • Phenol derivative
  • Radioactive elements
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8
Q

How do genetic differences affect the way carcinogens in smoke cause mutations?

A

Genetic variants can change how well our bodies break down carcinogens or repair DNA damage, which affects how harmful the smoke is to our DNA.

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9
Q

What is the P-450 enzyme

A

This enzyme family helps the body process toxins like procarcinogens (substances that become carcinogenic after being metabolised)

People with specific P-450 enzyme variants incur a greater risk of lung cancer

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10
Q

How do scientists test for DNA repair sensitivity

A

Individuals whose peripheral blood lymphocytes show more numerous chromosomal breakages after exposure to tobacco-related carcinogens are called ‘mutagen sensitive’

This means that their DNA repair systems are weaker, making them 10x more likely to develop lung cancer due to variation in genes involved in DNA repair.

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11
Q

What is the asbestos lung cancer risk epidemiology

A
  • Lung cancer it the most frequent malignancy in persons exposed to asbestos
  • Asbestos workers who do not smoke have a five times increased risk and those who smoke have a 50-90 times greater risk of developing lung cancer.
  • Among asbestos workers one death in five is due to lung cancer
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12
Q

What are the key steps in how asbestos exposure can lead to lung damage, fibrosis, and then lung carcinoma

A

1) Inhalation of Asbestos fibers

2) Immune cell activation and inhalation

3) Damage and cell death

4) Fibrosis development

5) Cancer pathway - mutations

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13
Q

What does the inhalation of asbestos fibers entail

A
  • Inhalation of asbestos particles/fibers and they deposit in the lungs
  • This causes oxidative stress in the lungs produces radicals like OH, O2-, H2O2, NO
  • This leads to epithelial cell damage
  • Activation of alveolar macrophages (Immune cells)
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14
Q

What happens during immune cell activation and inflammation

A

Macrophages try to clear the fibres but can’t digest them

This leads to:

  • Chronic activation of macrophages

And release of:

  • Protease (Breaks down tissue)
  • Cytokines and chemokines (Signal other immune cells)
  • Oxidants (causes further damage)
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15
Q

How does constant immune activation cause damage and cell death

A

There is a constant cycle of:
- Chronic inflammation
- Oxidative stress
- Cell death

Leading to:
- Matrix degradation (loss of normal lung structure)
- Chronic tissue injury

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16
Q

How is fibrosis developed during asbestos exposure

A

Macrophages start releasing fibrogenic factors like PDGF, IGF, EGF and TGFb

These would stimulate:
- Fibroblast recruitment and proliferation

  • Collagen deposition

This leads to asbestosis, a fibrotic lung disease

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17
Q

What does the long term result of chronic inflammation, continuous epithelial injury and regeneration and genetic mutations caused by oxidants lead to

A
  • Epithelial hyperplasia/metaplasia
  • A tumour-promoting environment - DNA damage and genomic instability leads to uncontrolled cell growth and survival
  • Progression to lung carcinoma
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18
Q

How is Radiation a carcinogen risk factor

A

It has damaging effects on DNA. If the cell survives after the DNA damage then this may transform into cancer. If the damage is too severe the cell will die and the latter is the desired outcome during radiation therapy

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19
Q

What is the epidemiology of radiation lung cancer risk factor

A
  • Lung cancer rates among uranium miners are 4x higher than those of the general population
  • Exposure to radon gas is also linked to increased lung cancer risk
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20
Q

What are the dominant oncogenes (gain-of-function) that are frequently involved in lung cancer:

A
  • EGFR
  • c-MYC
  • KRAS
  • c-MET
  • c-KIT
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21
Q

What are the commonly deleted or inactivated TSGs (loss-of-function)

A
  • p53
  • RB1
  • p16
  • multiple loci on chromosome p3
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22
Q

What is NSCLC

A

Non-small cell lung cancer

Most common type of lung cancer - account for about 80% of cases

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23
Q

What are the frequency of mutations that are found in NSCLC

A

Mutations in adenocarcinoma
- KRAS
- EGFR
- BRAF

Mutations in squamous cell carcinoma
- PTEN
- PIK3CA
- FGFR1

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24
Q

What are the common oncogenic mutations that are found in adenocarcinomas

A

EGFR
ALK
ROS1
MET
RET
BRAF
PI3K

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25
What is EGFR
Epidermal Growth Factor It is a receptor Tyrosine kinase found on the surface of cells
26
What happens once EGF binds to EGFR
- Autophosphorylation of tyrosine residues - Activation of downstream signalling pathways including: 1) RAS-RAF-MEK-ERK (cell proliferation) 2) PI3K-AKT-mTOR (cell survival and growth) 3) JAK-STAT (gene transcription)
27
How are EGFR mutations driver mutations
They cause uncontrolled cell division, survival and tumour growth Most commonly found in NSCLC particularly in adenocarcinoma
28
What are the common EGFR mutations
- Exon 19 deletion - Exon 21 point mutation: L858R - Exon 20 mutation: T790M - Exon 20 insertions These are mutations within the Tyrosine Kinase Domain
29
What are the molecular genetics of squamous cell lung carcinoma
Highly associated with exposure to tobacco smoke and harbours diverse genetic aberrations (Chromosome deletions involving tumour suppressor loci)
30
What are the tumour mutations present in squamous cell carcinoma
- TP53 - p53 protein overexpression - CDKN2A tsg, encoding cyclin-dependent kinase inhibitor p16 - Amplification of FGFR1, a gene encoding fibroblast growth factor receptor tyrosine kinase
31
What are the tumour mutations present in adencarcinoma
- EGFR - KRAS - MAPK -PI3K
32
What type of lung cancer is almost always associated with smoking and has the highest mutational burden
small cell carcinoma
33
Which two tumour suppressor genes are almost universally inactivated in small cell lung carcinoma
TP53 and RB
34
What genetic change is commonly seen when non-small cell carcinoma transforms into small cell carcinoma
Loss-of-function mutations in the RB gene
35
Why is RB inactivation significant in small cell lung carcinoma
Its essential for the development and transformation to small cell phenotype, highlighting its key role in this subtype
36
What are the subtypes of NSCLC
Adenocarcinoma - Arises in peripheral lung tissue - Often associated with EGFR, ALK and KRAS mutations Squamous cell carcinoma - Found centrally, near bronchial airways - May show keratinization and intercellular bridges
37
What is SCLC
Small Cell Lung Carcinoma It is very aggressive with high growth fraction and early metastasis - Originates from neuroendocrine cells of the lung - Not typically treated surgically due to rapid spread - recurrence is common - Universal inactivation of TP53 and RB - May express neuroendocrine markers like chromogranin A, Synaptophysin, and CD56
38
What are the clinical features of lung cancer
- Weight loss, cough, and haemoptysis - Metastasis sites includes: lymph node, bone, brain and liver
39
What are paraneoplastic effects
Paraneoplastic effects are symptoms that occur due to a cancer, but are not directly caused by the tumor itself or its metastases, instead resulting from substances released by the cancer cells that disrupt normal bodily functions.
40
What are the paraneoplastic effects due to the secretion of ectopic hormones
ACTH - small cell carcinoma producing features of Cushing Syndrome ADH - small cell carcinoma inducing hyponatremia PTH and PTHRP - squamous cell carcinoma producing hypercalcaemia Finger Clubbing and Hypertrophic pulmonary osteo-arthropathy
41
What are the local effects of spread of lung tumours
Pneumonia, Lobar collapse: airway obstruction caused by tumour Pleural effusion: Tumour spread into pleura Pericarditis, and cardiac tamponade: tumour spread to pericardium Paralysis of diaphragm: invasion of phrenic nerve Hoarseness of voice: invasion into sympathetic ganglia (miosis, ptosis, anhidrosis Rib destruction: invasion into chest wall SVC syndrome: compression of superior vena cava by tumour
42
What is Adenocarcinoma in-situ
AIS is a localised, small growth restricted to neoplastic cells along pre-existing alveolar structures, lacking stromal, vascular, alveolar space or pleural invasion or necrosis Non-invasive tumour therefore do not metastasise There is mucinous and non-mucinous sub-type
43
What is minimally invasive adenocarcinoma
Less than 30mm with predominantly lepidic pattern and less than 5mm invasion There is no invasion of lymphatics, blood vessels, or pleura There is no tumour necrosis There is no spread through airspaces Patients with MIA should have 100% disease-free and recurrence-free survival if the tumour is resected
44
What is the adenocarcinoma of the lung
Most common types of lung cancer with women and non-smokers Usually located in the peripheral lung
45
What is adenocarcinoma of the lung characterised by
Acinar, papillary, or lepidic growth patterns and mucin production by the tumour cells
46
What is the molecular genetics of adenocarcinoma
Mutations and amplification occur in various genes including EGFR gene. Patients with EGFR mutations have improved survival with EGFR/TK inhibitor treatment
47
What is Squamous Cell Carcinoma of the lung
- More commonly found in men and is correlated with smoking history
48
What is Squamous Cell Carcinoma of the lung characterised by
Keratinisation and/or intercellular bridges Mostly seen centrally in segmental bronchi but the incidence in the peripheral lung is increasing
49
What is the treatment for Squamous Cell Carcinoma
Anti PD-1monoclonal antibody (nivolumab) is used as 2nd line treatment. Works as a checkpoint inhibitor, blocking a signal that would have prevented activated T cells from attacking the cancer, thus allowing the immune system to clear the cancer.
50
What is Large Cell (undifferentiated) carcinoma
- Tumour comprises of sheets or nests of large polygonal cells with vesicular nuclei, prominent nucleoli, and moderate amounts of cytoplasm - Clear cell and/or rhabdoid cytological features may be present
51
What is a carcinoid tumour
- Low grade malignant epithelial neoplasm - Neoplastic cells have round regular nuclei with moderate amount of eosinophilic cytoplasm. Positive for neuroendocrine markers - Atypical carcinoids show increased mitosis/necrosis
52
What are metastatic tumours
- Most common site of metastatic neoplasm - Both carcinomas and sarcomas arising anywhere in the body may spread to the lung via blood or lymphatics - Colorectal cancer is the most common primary metastasizing to the lung - Usually multiple discrete nodules (cannon-ball lesions) are scattered throughout all lobes, more commonly at the periphery
53
What are lung cancer treatments
- Surgery - Chemotherapy - Radio therapy - Immunotherapy - Targeted therapy
54
What factors do the type of treatment received depend on
- The type of lung cancer (non-small cell/small-cell) - The size and position of the cancer - How advanced the cancer is - Overall health of the patient This is all decided on by the MDT meeting for each patient (surgeons, physicians, radiologist, pathologists and cancer care nurses)
55
What is the treatment if the patient is fit with localised NSCLC
Surgery followed by chemotherapy
56
What is the treatment is the patient is not fit with localised NSCLC
Radiotherapy sometimes combined with chemotherapy (chemo-radiotherapy)
57
What is the treatment if the NSCLC is spread too far
Chemotherapy or immunotherapy
58
What is the treatment if the cancer has a specific mutation
Biological or targeted therapy instead of chemotherapy
59
How SCLC treated
Chemotherapy - either on its own in combination with radio or immunotherapy
60
What is the pleura
A thin layer of tissue that covers the lungs and lines the interior wall of the chest cavity
61
What are Pleura mesotheliomas
Rare cancers that account of less than 2% of all malignancies 50% of patients die within 12 months of diagnosis and very few survive longer than 2 years
62
What are the risk factors of pleural mesotheliomas
- asbestos - erionite - genetic factors
63
How does exposure to asbestos cause pleural mesotheliomas
The majority of mesotheliomas are caused by occupation exposure to asbestos, with the strength of the relationship being dependent on fibre type When inhaled asbestos fibers lodge in the pleura, the lining of the lungs, causing inflammation, scarring, and potentially DNA damage that leads to cancer development over decades
64
How does Erionite cause pleural mesotheliomas
Naturally occurring fibrous mineral, can cause pleural mesotheliomas through a process involving chronic inflammation, the release of inflammatory mediators, and the potential for oncogenic transformation of mesothelial cells
65
What are the genetic changes that are present in mesotheliomas
- CDKN2a: codes for p16 and p14 (these are TSGs that regulate the cell cycle) - BAP1 - NF2 - TP53 In patients with germline mutations, including BAP1, exposure to even small amounts of asbestos can increase the risk of mesotheliomas
66
What are the clinical features for mesotheliomas
The initial presenting symptoms include dyspnoea, unilateral chest pain, cough, unintended weight loss, low grade fever and night sweats A frequent initial manifestation is symptomatic unilateral pleural effusion, with dyspnoea and a cough, which can resolve on effusion drainage
67
What are the macroscopic findings of mesotheliomas
- Tumour begins as pleural nodules that enlarge and extend over the surface of the lung, gradually encasing it - Growth typically occurs along the interlobular fissures and can inade the lung parenchyma, chest wall skeletal muscle or skin - Infiltration of the chest wall and intercostal muscles by the tumour causes severe pain
68
How are mesotheliomas classified
- Epithelioid - Sarcomatoid - Biphasic subtypes
69
What is the histology of epithelioid mesothelioma tissues
- Consists of cuboidal, columnar, or flattened cells forming tubular or papillary structures resembling adenocarcinoma - Immunohistochemistry helps in differentiating mesothelioma from adenocarcinoma - Calretinin, ck5/6, WT1 positive - Ber EP4 and BAP1 negative
70
What is the histology of sarcomatoid mesothelioma tissues
Has an appearance resembling fibrosarcoma - positive markers only for keratin
71
What is the histology of biphasic type mesothelioma tissues
contains both epithelioid and sarcomatoid patterns
72
Now with the rise of precision medicine, especially in adenocarcinoma (a subtype of NSCLC), what factors are taken into consideration when prescribing treatment
- Sub-classify what type of NSCLC it is (adenocarcinoma vs squamous) - Test for specific genetic mutations or rearrangements in the tumour This is critical because mutations have drugs that work specifically for them - leading to better outcomes and fewer side effects
73
How has high precision, gene guided treatment helped
- It has improved survival rates - Reduce unnecessary toxicity - Personalise therapy based on the tumours molecular fingerprint

Clinical Pathology in Action (18 decks)

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