Carcinoma of Bronchus

Question 1

Lung cancer is the 2^nd most common cancer in the UK w/ a peak incidence in the 50-60yo age group. It’s the most common cause of cancer death in both men + women - bc of poor prognosis (<10% of pts remain alive 5 yrs from diagnosis).

What are the causes of lung cancer?

Answer 1

• 80-90% lung carcinomas attributed to cig smoking
• lung cancer only develops in ~10% heavy smokers
• 10-20% lung cancers occur in non-smokers, causes:
  
  • industrial hazards eg. asbestos, arsenic, chromium, radiation
  • env exposure eg. radon gas (cornwall)
  • genetic factors eg. EGFR (epidermal growth factor receptor) gene mutations

Question 2

How is lung cancer histologically classified?

Answer 2

• Small cell lung cancer vs non-small cell lung cancer
• Small cell lung cancer → 15% cases + worse prognosis
• Non-small cell lung cancer:
  
  • adenocarcinoma → most common type, most non-smokers
  • squamous cell
  • large cell
  • alveolar cell carcinoma → not related to smoking
  • bronchial adenoma → mostly carcinoid

Differentiating is important due to different drugs available to treat different types

Question 3

The majority of lung cancers are carcinomas. They can be subdivided into 4 main groups + a misc category.

What are the different types/groups?

Answer 3

• adenocarcinoma (40%)
• squamous cell carcinoma (25%)
• small cell carcinoma (15%)
• others (eg. carcinoid, large cell neuroendocrine carcinoma etc)

also, don’t forget that lung is most common site of metastatic tumour (both carcinomas and sarcomas arising anywhere in the body may spread to the lungs)

Question 4

How does squamous cell carcinoma arise in the lung?

Answer 4

• strong association w/ smoking
• tends to arise in larger airways near hilum
• graded as: well, moderately or poorly differentiated
• well-defined ‘metaplasia-dysplasia-carcinoma’ sequence

Question 5

What are characteristics of adenocarcinoma?

Answer 5

• increasing in incidence (uknown reason)
• most common type of lung cancer in non-smokers
• although majority of these pts are smokers
• associated w/ mutations in EGFR gene
• tends to arise in peripheral smaller airways
• graded as: well, moderately or poorly differentiated
• premalignant lesion is called atypical adenomatous hyperplasia (equiv to dysplasia)
• it is asymptomatic

Question 6

What are characteristics of small cell carcinoma?

Answer 6

• strongest association w/ smoking
• usually arise in central location (APUD cells)
• highly aggressive tumour, notorious for rapid growth + early spread
• not graded (by definition, small cell carcinoma = high grade)
• no recognised precursor (premalignant) lesion
• associated w/ ectopic ADH + ACTH secretion → hyponatraemia, cushing’s, adrenal hyperplasia

Question 7

What are large cell carcinomas?

Answer 7

• undifferentiated carcinomas, poor prognosis
• cannot be otherwise categories
• lack morphological features of other forms of lung cancer
• typically peripheral + anaplastic

Question 8

In recent years there have been several important advances in understanding of the genomics of lung cancer. Some genetic mutations are targets for new therapies.

Use tyrosine kinase inhibitors as an example of this

Answer 8

• EGFR is a transmembrane tyrosine kinase that is mutated in between 10-50% of non-small cell carcinomas
• certain EGFR mutations are associated w/ response to tyrosine kinase inhibitors eg. gefitinib + erlotinib
• another genomic alteration seein in approx 2-5% of lung cancers is an inversion in the short arm of chromosome 2 -> results in fusion of EML4 gene w/ ALK gene -> results in EML4-ALK fusion tyrosine kinase - tumours with this mutation are associated w/ response to the TKI crizotinib

Question 9

Obtaining a histological/cytological diagnosis of malignancy is important prior to tx.

One reason for this is bc certain non-malignant processes (benign tumours, certain infection) can result in a mass lesion in the lung. Also, important to know the histological type of cancer that the patient has for management purposes + prognosis.

What investigations are best for the following?

• central lesions
• peripheral lesions

Answer 9

• central lesions (ie near hilum) -> bronchoscopy sampling
  
  • biopsy (histology) and/or washings, brushings (cytology)
• peripheral lesions -> CT-guided sampling
  
  • biopsy (histology) and/or FNA (cytology)

Question 10

How is immunotherapy in targeting genetic mutations for lung cancer?

Answer 10

• immune checkpoints affect immune system functioning
• can be stimulatory or inhibitory
• tumours can use checkpoints to protect themselves from immune attacks
• PD-L1 is a key regulator of T cell function
  
  • binds to PD1 on T cells + inhibits their activity
  • PD-L1 expressed by some cancer cells
  • enables them to inhibit T cells that might attack them
• PD1 and PDL1 inhibitors (monoclonal abs) eg pembrolizumab have been developed for non-small cell lung cancer
• the antibodies bind to either PD-1 or PD-L1 + therefore blocks the interaction
• therefore, immune system able to mount response to tumour cells + kill them

Question 11

How is lung cancer staged?

Answer 11

• both small + non-small cell carcinoma staged using TNM
• imaging has a very important role in staging lung cancer:
  
  • CT good for T (tumour) staging - less sensitive for detection of involved lymph nodes + distant mets
  • PET or PET-CT enables more accurate staging of N (nodes) + M (mets) prior to surgery

Question 12

What is Pancoast’s tumour?

Answer 12

• in apex of lung
• involves 8^th cervical + 1^st and 2^nd thoracic nerves
• may manifest as Pancoast’s syndrome
  
  • shoulder pain radiating in an ulnar distribution down arm
• or Horner’s syndrome

Question 13

What are local symptoms and signs of lung cancer?

Answer 13

• cough (involvement of central airways) - most common initial presenting symptoms
• haemoptysis (bleeding from tumour)
• stridor/wheeze (large airway obstruction)
• hoarse voice (invasion of left recurrent laryngeal nerve)
• breathlessness (large airway obstruction and/or development of associated pleural effusion)
• chest wall pain (chest wall involvement)
• non-resolving pneumonia (tumours may partially obstruct airways leading to infection)

Question 14

What is the link with SVC obstruction and lung cancer?

Answer 14

• obstruction of SVC usually due to right-sided lung tumour (often small cell carcinoma)
• causes increased venous pressure
• results in interstitial oedema + retrograde collateral flow
• collateral venous return to heart from upper half of body is through azygos venous system, internal mammary venous system and long thoracic venous system
• despite collateral pathways, venous pressure is almost always elevated
• most common symptoms = SoB, facial swelling, head fullness, cough, arm swelling, chest pain, dysphagia, hoarseness, stridor
• SVC obstruction = oncological emergency bc may lead to laryngeal oedema, cerebral oedema or decreased CO

Question 15

What is Horner’s syndrome characterised by?

Answer 15

• endopthalmos (eyeball depression)
• ptosis (droop) of upper eyelid
• miosis (pupil constriction)
• anhidrosis (absence of sweating)

Many causes of Horner’s syndrome, of which Pancoast’s tumour is one. Due to sympathetic nerve infiltration by tumour, particularly T1

Question 16

What are systemic symptoms of lung cancer?

Answer 16

• refer to general effects of tumour mass on body
• giving rise to non-specific constitutional symptoms
• weight loss, lethargy, vague sense of ill health

Question 17

What are distant mets?

Answer 17

• lung cancer may metastasise to any organ of body
• produce symptoms that may form the presenting complaint
• bone, liver, CNS

Question 18

Hypercalcaemia is a paraneoplastic manifestation of lung cancer. How is this so?

Answer 18

• more common w/ squamous cell carcinomas
• as a paraneoplastic effect, is is due to production of a PTH-related peptide (PTH-rP) by tumour cells
• -> release of calcium from bone

remember that hypercalcaemia in the setting of lung cancer is usually due to bony metastases (not a paraneoplastic syndrome)

Question 19

How does SIADH (syndrome of inappropriate ADH secretion) result as a paraneoplastic manifestation of lung cancer?

Answer 19

• mainly seen w/ small cell carcinomas
• in half cases there is in inappt secretion of ADH by tumour cells
• in other half, there is inappt secretion of ADH from posterior pituitary bc of altered/defective chemoreceptor control
• the inappt secretion of ADH -> inappt water reabsorption
• –> low serum [Na⁺], low serum osmolality + overhydration

Question 20

How is ectopic ACTH secretion from tumour cells a paraneoplastic manifestation of lung cancer?

Answer 20

• typically associated w/ small cell carcinomas
• inappt secretion of ACTH by tumour cells
• leads to bilateral adrenal cortical hyperplasia
• and secretion of inappt amounts of cortisol
• chief manifestations: thirst + polyuria
• typical features of Cushing’s syndrome rarely seen, as death often occurs before features fully develop

Question 21

LEMS is another paraneoplastic manifestation of lung cancer. What is lambert eaton myasthenic syndrome (LEMS)?

Answer 21

• typically associated w/ small cell carcinomas
• autoantibodies block voltage gated calcium channels in presynaptic membrane
• thereby blocking ACh release
• in about 50% cases, underlying malignancy present (ie. paraneoplastic syndrome)
• it’s thought that stimulus for autoantibody formation in these cases may be expression of same calcium channel in tumour cells

Question 22

Lung carcinomas are divided into two management groups.

How is small cell lung carcinoma (SCLC) managed?

Answer 22

• highly aggressive tumours in which extensive mets are usually already present at time of diagnosis
• so surgery has little role in management of SCLC
• some patients with very early stage disease considered for surgery
• most pts get chemotherapy + radiotherapy
• initially, tumours are responsive to chemotherapy
• however, after a period of time (few months), tumours become chemoresistant + progresses rapidly

Question 23

How is non-small cell lung carcinoma (NSCLC) managed?

Answer 23

• group encompasses other histological type (eg. squamous carcinoma, adenocarcinoma etc)
• the tumours generally managed in similar way, depending on stage + other factors
• only 20% suitable for surgery
• mediastinoscopy performed prior to surgery as CT doesn’t always show mediastinal lymph involvement
• curative or palliative radiotherapy
• poor response to chemotherapy

Question 24

What is mesothelioma?

Answer 24

• malignant tumour of pleura
• associated w/ asbestos exposure
• mesothelium = cell lining of pleura
• usually long latency period (in order of 40yrs) between exposure + development of tumour

Question 25

What is the typical presentation of mesothelioma?

Answer 25

• men aged 60+
• breathlessness
• chest pain
• pleural effusion

Occupational history super important for diagnosis

Question 26

How is the diagnosis made for mesothelioma?

Answer 26

• cytological examination of pleural fluid
• or on histological examination of a pleural biopsy
• tumour spreads extensively within chest wall, encasing entire lung
• mesothelioma is not graded (by definition it is highly aggressive)
• mesothelioma has a dismal prognosis - mean survival is around 18 months from diagnosis

Question 27

Apart from mesothelioma, another important asbestos-related disease is lung cancer. How is this so?

Answer 27

• asbestos alone increases risk of lung cancer
• smokers who are also exposed to asbestos have risk of developing lung cancer that is greater than the individual risks from asbestos and smoking adding together (ie. the risk factors are synergistic)

Question 28

What is asbestosis?

Answer 28

• one type of diffuse parenchymal lung disease
• diffuse fibrosis of lung parenchyma (ie. lung fibrosis) due to asbestos
• v high levels of asbestos exposure required to cause lung fibrosis + so asbestosis is rare
• in contrast, the pleural changes caused by asbestos occur at lower levels of exposure and so are much more common
• pts w/ asbestosis usually present w/ gradually worsening dyspnoea which terminates in chronic respiratory failure