L16 Lung Cancers

Question 1

Epidemiology of lung cancer

Answer 1

5th most common cancer, but most common cause of cancer death in NZ (due to disease biology + late presentation + unmet need for new therapies)
Most patients aged 50–80, with peak age 60–70 (issue as popn increases)
Male predominance (2:1) but this is decreasing (more smoking amongst women in certain ethnic groups)
Strong link with smoking (85%) (carcinogen exposure + induce cancer with highest rates of oncogene mutations)

Question 2

Statistics re Epidemiology of lung cancer

Answer 2

Most common: 5. Lung 9.9%
Leading causes of death: 1. Lung 18.2%
Leading cause of cancer death for females: 3. Lung 15.5% (behind breast and colorectal)
Leading cause of cancer death for males: 1. Lung 20.7%
Cancer Deaths US (25-30%)
-Men: 1. Lung + Bronchus 28%
-Women: 1. Lung + Bronchus 26%

Question 3

Lung Cancer Pathogenesis

Answer 3

Strongest link is with smoking
-90% of lung cancer occurs in smokers - squamous and small cell lung cancer
-Strong statistical (epidemiological data), experimental (biomedical( effects of carcinogens + mutations)) and clinical evidence supports
-Linear correlation years smoking and incidence lung cancer
-Other genetic (SNPs/Polymorphisms increasing or decreasing risk) and
environmental factors

Question 4

Lung Cancer Cellular/Molecular level

Answer 4

Progressive transformation of benign bronchial epithelium into neoplasm
Stepwise accummulation of molecular changes including (tyrosine kinase receptors and transcriptional regulators)
-3p deletions,
-p53 mutations,
-K-ras mutations
-carcinogen exposure in enviro, causes series of mutations in bronchial mucosa/epithelial cells –> dysplastic –> localised carcinoma –> invasive –> metastatic

Question 5

Histopathologic classification of 1 primary lung cancer /Pathology

Answer 5

Histopathologic classification of 1 primary lung cancer (morphological)

• Small cell lung cancer (20-25%) (round. derived from neuroendocrine precursor cell)
• Non small cell lung cancer (70-75%) (squamous cell carcinoma, adenocarcinoma, large cell carcinoma) (different molecular changes and diff. cell of origin)
• Combined pattern (5-10%) (non-clear features of either)

Question 6

Basis of Histopathologic classification of 1 primary lung cancer

Answer 6

Histopathologic classification of 1 primary lung cancer (morphological)

1. Reflects cell of origin in lung
2. Differences at a molecular level (different patterns of genetic mutation b/w subtypes)
   - K-ras, EGFR and ALK mutations in NSCLC
   - Implications for targeted therapy
3. Clinical and therapeutic implications

Question 7

Molecular pathology of lung cancer

Answer 7

Had different morphologic classifications of lung cancers for a long time. predicted for different behaviours.
-now at molecular level noticing different gene mutation patterns, cause different clinical features and presentation
Extra: 1. Adenocarcinoma (not re. to smoking. more peripheral lesions. evolve from alveolar cells forming glandular structures)
-tyrosine kinase mutations receptor signalling pathway
2. Small cell lung cancer (neuroendocrine cell precursor. mutations in cell cycle regulators (retinoblastoma + p53). aggressive. proximally in major airways)
3. Squamous cell lung cancer. mutations in nox gene. cell differentiation

Question 8

Targeted Therapy in Lung cancer

Answer 8

Non-small cell cancer (esp. adenocarcinoma) tyrosine kinase pathway mutations (esp. epidermal growth factor receptor + ALK gene pathway) (constitutively activated signalling pathways causing increased proliferation, reduced cell death, angiogenesis, propensity for invasion and metastatic spread)
In NZ Pharmac have funded two tyrosine kinase inhibitors for non small cell lung cancer with EGFR mutations:
-Erlotinib
-Gefitinib
(understanding 1. morphology and 2. genome profile/molecular pathology of cancer leading to therapeutic implications + targeted therapy)

Question 9

Clinicopathologic features of lung cancer: Local Effects

Answer 9

cough,
dyspnoea,
haemoptysis (lesion, BV exposure, cough blood),
chest pain (close to innervated area),
obstructive pneumonia (secretions blocked and not cleared, risk of infection distal to obstruction –> pneumonia)

Question 10

Clinicopathologic features of lung cancer: Local Spread

Answer 10

• (malignant) pleural effusions (distal nodule. fluid accumulate w. cancer cells),
• nerve entrapment eg Horners syndrome

Question 11

Clinicopathologic features of lung cancer: Mediastinal spread

Answer 11

obstruct/impinge on function of other structures in mediastinum

• SVC(superior vena cava) obstruction, (**think of features)
• nerve entrapment syndromes eg recurrent laryngeal nerve palsy (horse voice)

Question 12

Clinical Scenario: haemoptysis and abnormal chest xray
A 65 (lung cancer age group) year old Samoan man returns to the GP clinic where you are on your attachment. He has had a prolonged cough and the GP arranged a chest X-ray which has shown a 2.5 cm diameter cavity within an area of confluent shadowing in the superior segment of the right lower lobe. He has come back for the result and reports that he coughed up some blood recently. He is a long-term smoker (risk factor) and has a heavy consumption of alcohol.

Answer 12

• could be primary lung cancer

- could be infective (e.g. pulmonary TB or pneumonia w. cavitation)

Question 13

SVC obstruction

Answer 13

obstruct/impinge on function of other structures in mediastinum
- SVC(superior vena cava) obstruction,
-veins are obstructed and distended
-engorged and distended (45 degress –> 1-2cm above angle of sternum/ at clavicle/ doesnt move with respiration) Jugular veins/ JVP Jugular Venous Pressure
-venous networks open up to bypass the obstruction
-facial fullness and oedema and swelling
-pladder/congestion/redness of face
Arms above head= red face= increased obstruction, block off all venous return
Large enough mass can obstruct trachea
Confirm= lung biopsy (difficult as is pressing on trachea + anaesthetic)

Question 14

Horner’s Syndrome

Answer 14

Tumour mass in Apex of Lung

• sympathetic nerve branch goes across apex of lung
• if impinged across lung apex by apical tumour
• Ptosis of eye + reduced sweating in forehead + meosis dilation of pupil
• often asymptomatic

Question 15

Clinicopathologic features of lung cancer: nerve entrapment

Answer 15

Hoarse voice secondary to recurrent laryngeal nerve entrapment
-tumour on Left side extending into hilum
-recurrent laryngeal nerve loops around mediastinum, under aortic arch, tumour mass pushes on
-impaired ability for vocal cord
-High E = brings vocal cords together = cannot do it if impaired
=feature of local spread

Question 16

Metastatic spread

Answer 16

Lung cancers often have metastatic spread at diagnosis

• regional lymph nodes eg hilar
• extranodal eg brain (neurological symptoms with CNS lesion), bone (pathological fracture/bone pain), liver and adrenal (incidental finding)
• presentation to clinician may be from secondary spread rather than primary lesion
• to a screen for primary lung lesion

Question 17

Paraneoplastic syndromes

Answer 17

Paraneoplastic syndromes

a. -Small cell lung cancer (produce cytokine/endocrine factors which cause systemic syndrome) eg Cushing syndrome (moon face + osteoporosis. effects of long term steroid exposure, increased cortisol production secondary to ACTH); Inappropriate ADH secretion (low Sodium, hypercalcemia)
b. -Non small cell lung cancer eg hypercalcaemia secondary to PTH-rp (obstruction to normal PTH parathyroid hormone related peptides)
c. -Finger clubbing
d. constitutional non-specific Systemic features eg weight loss, cacexia, general malaese, fatigue

Question 18

Finger clibbing

Answer 18

Loss of nail fold
Advanced cases: -can get club shape/expansion around nail case/bone
-abnormal cytokine release?
-seen in lung cancer, other pulmonary pathologies (bronchiectasis)

Question 19

NSCL: Squamous cell carcinoma

Answer 19

30% of all lung cancer
Strong link with smoking (mutaitons induced by carcinogens in cigarette smoke)
-Injury to bronchial epithelium
-Sequence of dysplasia –>, carcinoma in situ –> , invasive tumour

Question 20

NSCL: Squamous cell carcinoma Pathology

Answer 20

Most arise centrally in major or segmental bronchi (mucosa)
Firm, grey, ulcerated lesions in bronchial wall (assoc. with hemoptysis as often necrosis on surface) (chronic cough coughing up blood)
Extend through into adjacent lung parenchyma
Often show necrosis, cavitation
Microscopy shows variable differentiation, with keratin pearls, intercellular bridging
-gross level bronchoscopy (flexible telescope)

Question 21

Adenocarcinoma lung

Answer 21

30% of invasive lung cancer
Most common type in females
Most common lung cancer seen in non smokers
Tends to arise in the periphery (alveolar cells)
Irregular masses in lung periphery (chest pain, pneumonia, horner syndrome lesion), 2-5 cm but can be quite large
Often in pleural fibrosis or scars
Architecture reflects part of the respiratory tract tumour arises in but subtypes of acinar, papillary, solid with mucinous formation and bronchioalveolar plugging (patterns of morphology all in attempt to form glandular structure)
-different mutation profile (EGFR gene mutations)
-Bronchioalveolar Carcinoma

Question 22

Bronchioalveolar Carcinoma

Answer 22

Subtype of adenocarcinoma arising existing alveolar walls
Up to 5% of all lung cancers (infrequent)
Grossly maybe single or multiple nodules or diffuse infiltration

Question 23

Small Cell Carcinoma

Answer 23

20% of invasive lung cancer
Very aggressive
Also strongly linked with smoking
Highly malignant, epithelial tumour but exhibits neuroendocrine features
Paraneoplastic syndromes common (cushings, hyperneutremia from SAADH)
Arise as peri-hilar mass (central not periphery), often with lymph node invasion (rapidly growing often out growing blood supply, therefore necrosis/cell death in centre)
Frequently shows haemorrhage (secondary bleeding) and necrosis on cut section
Microscopically sheets of small round or spindle shaped cells, high mitotic rate (rapidly dividing and growing cells)
-masses of small round cells

Question 24

Other lung cancers

Answer 24

1. Large cell carcinoma
   Poorly differentiated without features of squamous cell or adenocarcinoma; 10% of lung cancers
2. Carcinoid tumours (presents at multiple sites)
   Neuroendocrine tumours but usually “silent”
   Approx. 2% of lung tumours; not related to smoking

Question 25

Pulmonary metastatic disease

Answer 25

Most common neoplasm of the lung (metastatic disease from colorectal, breast)
Typically multiple (tumours) and circumscribed
Histology that of the primary tumour (usually primary tumour known, diagnosis made from that)

Question 26

Tumours of the pleura

Answer 26

1. Malignant mesothelioma (mesothelial cells in pleura)
   Tumour of mesothelial cells
   Complication of asbestos fibre exposure (plumbing, building, engineering), long latency
   -pipes clad in aesbestis fibres, which are carcinogenic, cause pulmonary & pleural fibrosis, predispose pathogensis of malignant tumours of pleural surface
   -health concern of public demolition of roofing materials (contain asebestos and are released)
2. Pathology of mesothelioma
   Encases and compresses the lung
   Microscopically has both epithelia and sarcomatous elements
   -difficult to treat as rise off pleural surface

Question 27

Lung Cancer summary

Answer 27

Most common cause of cancer death
Strong link to smoking
Pathologic subtypes
-Small cell lung cancer
-Non small cell – squamous, -adenocarcinoma, large cell
-Prognostic significance (clinical, molecular and prognostic)
Molecular subtypes – implications for therapy and prognosis
-moving towards moelcular typing
Clinico-pathologic features
-Local effects eg haemoptysis
-Local invasion eg pleural effusion
-Metastatic spread eg bone, brain
-Paraneoplastic features eg clubbing, hypercalcaemia