Lung Cancer

Dr. Bhupendra kaushik

Dr. deepti sharma
MU-2
 Lung Cancer
• WHO defines Lung Cancer as tumor arising from the respiratory epithelium
(Bronchi, Bronchioles and Alveoli)

• Rare before 1900 with fewer than 400 cases.

• Mid 20th Century, leading cause of cancer related deaths worldwide

• For 2019, the estimates for lung cancer overall in the United States are
228,150 new cases and 142,670 deaths.1

• According to WHO statistics about 1.69 million death from lung cancer
per year worldwide.

• In India, approximately 63,000 new cases are reported each year.2

1-American cancer society. Cancer facts &figures 2019

2-Indian journal of cancer 49 (1) ;74-81 July 2012
 Epidemiology
About 1.35 million new cases diagnosed worldwide each year
Canadian Cancer Statistics 2015
Causes and Risk factors of Lung Cancer
 Risk Factors
• Cigarette smoking

• Second-hand smoke

• Occupational exposure (asbestos, motor vehicle emissions,

pollutants, radon-alpha radiation)

• Genetics

• Low level radiation

• Smoking and low intake of beta carotene.

 Cigarette Smoking
• Smoker –more than 100 cigarette smoked per life time

• Former smoker-more than 100 cigarette smoked per life time, quit
for more than 1 year.

• Never smoker-less than 100 cigarette smoked per life time

• 10 fold more risk of cancer in smoker than non smoker.

• Former smoker have a 9-fold and smoker have 20 fold increased risk
of developing lung cancer compared to non smoker..

• A large scale genomic study suggested that, one genetic mutation

for every 15 cigarettes smoked.

•
Harrison’s 20th addition 2018
 WHO Classification of Lung Tumors,2015

>>>WHAT’S NEW?

The most significant changes in this edition involve:-

(1) Use of immunohistochemistry throughout the classification

(2) A new emphasis on genetic studies, - integration of molecular testing

to help treatment strategies for advanced lung cancer patients

(3)A new classification for small biopsies and cytology

 Lung Cancer

• Four histologies account for approximately 90% of all epithelial lung

cancers. are:-

1.Small Cell Lung Cancer (SCLC) (20%-25%)

2.Adenocarcinoma(40%-50%)

(NSCLC)(~80%)
3.Squamous Cell Carcinoma(30%-40%)

4.Large Cell Carcinoma(15%-20%)

Diagnostic Lung Immunohistochemistry

Small cell lung cancer Adenocarcinoma

• Ck+ • Ck+
• TTF1+ • Ck7+
• CD56+ • TTF1+
• Chromgranin+ • Napsin-A
• Synaptophysin + • Neuroendocrine (-)
Squamous cell ca Large cell ca
• Ck+ • Ck+
• p63 or p40 • TTF1 unusual
• Ck5/6+ • Neuroendocrine (-)
• Ck7 unusual
 Small cell lung cancer
• Most aggressive lung cancer.
• Accounts 20-25% of all lung cancer.
• Central in location.
• 90% found in smokers.
• 70% causes metastasis.
• associated with Paraneoplastic
syndrome: ACTH, SIADH, Eaton Lambert.
 Squamous cell carcinoma
• Most common type in India
• Central in location.
• 95% found in smokers.
• 60% causes metastasis.
• more often a/w Cavitation
• Pancoast tumor
• Paraneoplastic syndrome:
hypercalcemia (ectopic PTH rP)
 Adenocarcinoma

• Most common in developed countries

• peripheral location.
• 50% smokers.
• 80% metastasis.
• Hypercoagulability.
• Hypertrophic pulmonary
osteoarthropathy.
 Large cell carcinomas

• Peripheral location
• 15-20% of all lung cancers
• 90% smokers.
• 80% metastasis.
 CLINICAL MANIFESTATIONS

• Lung cancer may be asymptomatic and may only be

found in routine x-ray.

• Signs and symptoms depend upon the location, size of

the tumor, degree of obstruction and existence of

metastasis.
Presenting Sign And Symptoms of Lung
Cancer
CLINICAL MANIFESTATIONS……..

a) Local manifestations

b) Metastatic Manifestations

c) Non Metastatic systemic Manifestations ( includes

paraneoplastic syndrome)
 CLINICAL MANIFESTATIONS…….

A. LOCAL MENIFESTATIONS
1. Cough – most common symptom
2. Haemoptysis- cardinal symptom
3. Breathlessness
4. Chest Pain-
(i) Pleuritic Pain- Tumour spread to pleural space
(ii) Continuous Pain- Malignancy spread beyond pleura
(iii) Shoulder pain- Due to nerve compression by tumour
towards lung apex.
 CLINICAL MANIFESTATIONS…….

B. METASTATIC MANIFESTATIONS – Intrathoracic

1. Superior vena cava syndrome (SCLC)
2. Pleural effusion (dyspnoea)
3. Recurrent Laryngeal nerve palsy (Hoarseness of voice)
4. Phrenic nerve palsy (Diaphragmatic paralysis)
5. Pancoast syndrome usually associated with squamous cell
carcinoma, it compresses lower part of brachial plexus (C8, T1 and
T2)) and causes shoulder pain, characteristically radiates in ulnar
distribution of the arm.
6. Horner Syndrome (due to invasion of paravertebral sympathetic
chain)
 CLINICAL MANIFESTATIONS…….

B. METASTATIC MANIFESTATIONS – Extra thoracic

(More common with small cell lung cancer)
1. Brain- SCLC > squamous > adeno > large cell
Presents with headache, vomiting, blurred vision, seizure.
2. Skeletal- Metastasis to vertebra and ribs
SCLC > NSCLC
3. Spinal Cord- compression causes pain
4. Adrenal- metastasis common with small cell carcinoma
5. Hepatic- liver is enlarged, hard and nodular.
 CLINICAL MANIFESTATIONS……..

C. Non metastatic systemic manifestations-paraneoplastic (PNS)

• Most common tumour producing PNS are lung cancer.
• More frequently associated with SCLC.
• Size of primary tumour has no impact on the extend of PNS.

1. Endocrine syndrome :-
a) Cushing syndrome- Lung cancer most common source of ectopic
secretion of ACTH.
SCLC(85%) > Carcinoid tumour(10%) > adenocarcinoma(5%)
b) Hypercalcemia- Associated with squamous cell carcinoma which
secret PTH related peptides.
c) SIADH- Mainly associated with SCLC.
 CLINICAL MANIFESTATIONS…….

2. Neurological- associated with SCLC

a) Eaton Lambert Syndrome- due to IgG Autoantibodies against P/Q
calcium channels at neuromuscular junction.
b) Encephalomyelitis and Sensory neuropathy
c) Paraneoplastic cerebellar Degeneration

3. Haematological
a) Granulocytosis – from 10000 to 25000 /microL
b) Thrombocytosis – 500,000/microL

4. Skeletal – Digital clubbing & hypertrophic osteoarthropathy

Diagnostic test &
Staging Workup

• Complete history and physical examination

• CBC, DLC

• Serum electrolytes -Hyponatremia is an adverse prognostic factor in SIADH.

• Serum calcium -Elevated Ca+ and ALP suggest bone metastasis

• Liver function test.

• RFT -increased uric acid level and impaired RFT indicates potential for tumor lysis

syndrome with therapy.

 Diagnostic tests & Staging Workup……

• Serum LDH -elevation indicates increased tumor mass and high cell turnover
-> adverse prognostic factor.
• Serum alkaline phosphatase (ALP)
• Chest X-ray PA and lateral view
• Sputum for malignant cytology
• Pulmonary function test
• CECT chest and abdomen.
• Bronchoscopy
• MRI brain with contrast
• Pleural fluid for malignant cytology
• Bone scanning (for bone metastasis if calcium and ALP elevated even in the
absence of symptoms)
• Bone marrow aspiration and biopsy.
• PET-CT scan
 Pulmonary function test

• Patient with FEV 1 of more than

2 liter or more than of 80% of
predicted value, can tolerate a
pneumonectomy.
• FEV1 1.5 Liter have adequate
reserve for a lobectomy.
• FEV1 of less than 1 liter is
contraindication for surgery.
• Maximum oxygen consumption
( Vo2max). A Vo2max less than 15
ml /kg/min predicts for a
higher risk of post-op
complication.
pulmonary lab: SMS Hospital ->
CECT scan chest of a patient of small cell carcinoma
showing a thrombus in superior vena cava (short arrow).
Note pleural effusion on right side and dilated azygous
vein (long arrow) due to blood diversion.
Coronal contrast CT scan showing a right hilar
bronchogenic carcinoma (short thick arrow) with metastasis in the left
adrenal gland (long thin arrow)
 PET Scan

Based on glucose metabolism, measuring the uptake of

18F- Flurodeoxyglucose (FDG)

Tumor cell -> take-up -> hotspot

Useful to diagnose tumor > 15mm in diameter
Standard uptake value(SUV) of >2.5 on PET is highly suspicious of malignancy.
False negative –
• Diabetes
• Lesion < 8mm
• Slow growing tumors (carcinoid or well differentiated adenocarcinoma)
False positive – certain infections and granulomatous disease(TB)

Thus PET should never be used alone, confirmation with tissue biopsy is
always required.
PET CT is superior to PET
PET CT is inferior to MRI for brain Mets.
Harrisons 20th edition 2018.
 TNM Staging (8th Edition)
Tx Primary tumor cannot be assessed

T0 No evidence of primary tumour

T1 Tumour 3 cm or less in greatest diameter surrounded by lung or visceral pleura, without evidence of
main bronchus

T1a(mi) Mininally invasive adenocarcinoma

T1a Tumour 1 cm or less in greatest diameter

T1b Tumour more than 1 cm but not more than 2 cm

T1c Tumour more than 2 cm but not more than 3 cm

T2 Tumor more than 3 cm but not more than 5 cm; or tumor with any of the following features: Involves
main bronchus (without involving the carina), invades visceral pleura, associated with atelectasis or
obstructive pneumonitis that extends to the hilar region

T2a Tumour more than 3 cm but not more than 4 cm

T2b Tumour more than 4 cm but not more than 5 cm

T3 Tumour more than 5 cm but not more than 7 cm or one tha directly invades any of the following:
chest wall, phrenic nerve, parietal pericardium, or associated separate tumour nodule(s) in the same
lobe as the primary

T4 Tumors more than 7 cm or one that invades any of the following: diaphragm, mediastinum, heart,
great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor
nodule(s) in a different ipsilateral lobe to that of the primary.
 TNM Staging (8th Edition)
Reasonal Lymph Nodes (N)

Nx Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and
intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral
scalene or supraclavicular lymph node(s)

Distant Metastasis (M)

M No distant metastasis
0
M Distant metastasis
1
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural or
pericardial nodules or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis in a single organ
M1c Multiple extra thoracic metastases in one or several organs

International Association for the Study of Lung Cancer, 2015

TNM Staging (8th Edition)
 Modes of treatment

• Surgery
• Chemotherapy
• Radiotherapy
• Targeted therapy
• Immunotherapy
 Outline for Management of NSCLC

Stage I and II NSCLC

(resectable)

Operable Inoperable

Surgical Resection
SBRT
(Lobectomy)

Stage I and IB Stage IB and II Stage III

(&amp;lt; 4cm primary) (&amp;gt; 4cmprimary) (Occult N2)

Adjuvant Chemotherapy
No Adjuvant Rx AdjuvantChemoradiation
( 4 cycles platinum based)
Outline for management of SCLC
 Types of Surgery

Lobectomy &amp; Pneumonectomy

Wedge Resection Segmentectomy

Video Assisted Thoracoscopic Surgery

Mediastinal Lymphadenectomy

Sleeve Lobectomy &amp; Segment Resection

 Chemotherapy

• To cure cancer:
1. First line
2. Maintenance
• continuation switch
• maintenance
3. Second line
 FIRST LINE CHEMOTHERAPY
HISTOLOGY CT ADD ON DRUG
NSCLC PLATINUM BASED 3 RD GEN DRUG
DOUBLET
SQUAMOUS CELL ALL EXCEPT PEMETREXED

ADENOCARCINOMA PEMETREXED

LARGE CELL PEMETREXED

UNDIFFERENTIATED ALL EXCEPT PEMETREXED

SCLC PLATINUM BASED ETOPOSIDE OR

DOUBLET IRINOTECAN

3RD GEN DRUG- GEMCITABINE, PACITAXEL, DOCEETAXEL, PEMEXTRED, VINORELBINE

MAINTENANCE CHEMO.

• After 4-6 cycles of 1st line chemo.

• Pemetrexed
• Bevacizumab
• Erlotinib

2ND LINE CHEMO.

• Docetaxel
• Pemetrexed
• Erlotinib
 Radiotherapy

Curative intent ablative radiotherapy

• SBRT- stereotactic body radiotherapy

• stage I & II if inoperable

Post operative radiotherapy

• incompletely resected tumors or positive mediastinal nodes

• Tumor doses of 60 to 70 Gy in 2-Gy fractions
 Targeted Therapies

Potential molecular targets in squamous NSCLC: EGFR expression1

Ligand Metastatic
EGFR EGFR spread
activation dimer

Cell survival

Angiogenesis

Blood
Tumor vessel

Proliferation
 Targeted Therapies…..

Identify and attack certain type of cancer cells with less harm
to normal cells.

1. Anaplastic lymphoma kinase(ALK) inhibitors:-

(i) Ceritinib
(ii)Crizotinib
(iii) Alectinib
(iv)Brigatinib Recently approved
(v)Lorlatinib (can cross BBB)
Targeted Therapies……

2. EGFR inhibitors:- Block the activity of the protein called EGFR

• (i) Afatinib
• (ii) Dacomitinib
• (iii) Erlotinib
• (iv)Gefitinib
• (v) Osimertinib
• (vi)Necitumumab
 Targeted Therapies…….

3. ROS-1 inhibitors:- ROS-1 involve in cell signalling and cell growth.

Crizotinib-is approved for lung cancer.

4. BRAF inhibitors:- Protein B-Raf involved in sending signal in cell &

cell growth altered protein NSCLC
Combination of Debrafanib(BRAF inhibitors)
& Trametinib(MET protein inhibitor) approved for
NSCLC
 Immunotherapy…..

• Clinical trials are on going for to look out at new combination of

immunotherapy with or without chemotherapy to treat lung cancer.

An Immune Checkpoint inhibitor:-

• Blocks proteins on immune system cells which then allow them to

fight cancer.
• These drugs target the protein PD-L1 and PD-1
• Patients whose tumour test high for PD-L1 are more responsive to
this therapy, but more studies needed.
 Immunotherapy………
• Immune checkpoint inhibition for treating lung lung cancer
are :
• Atezolizumab
• Durvalumab
• Nivolumab
• Pembrolizumab
 Immunotherapy…….

• Drugs available in India and approved by drug controller general

of India for stage 4 lung cancer patients.
• pembrolizumab (keytruda)
• nivolumab (opdivo,opdyta)
• Atezolizumab(tecentriq)

• Recently , another check point inhibitor –

durvalumab (imfinzi) showed efficacy in stage 3 inoperable lung
cancer. The drug will be launched soon in India.
PALLIATION THERAPY
TO RELIEVE ENDOBRONCHIAL OBSTRUCTION, IMPROVE DYSPNEA,PAIN

& CONTROL HEMOPTYSIS.

TYPES

Photo resection with NAD: YAG laser

External beam radiotherapy

Stereotactic body radiotherapy

Repeated thoracocentesis / pleurodesis

Pain management-start with non opioids analgesic, then weak opioid

agonists followed by strong opioids agonists.