Lung Cancer

EPIDEMIOLO
GY
Globally, the most frequently diagnosed cancer is
lung cancer(11.4%)
For men, lung cancer is the most prevalent form of
cancer and third for women following breast and
colorectal cancer
 Mortality from lung
cancer
Lung cancer is at present the 6th leading cause of mortality
worldwide among all diseases and the leading cause of
mortality among all cancers
 AGE GROUP OF
PRESENTATION
More than 65% of patients with lung cancer are more than 65 years, mean time
at the age of diagnosis is 71 years

LUNG CANCER PREVALANCE

0.35

0.3

0.25

0.2

0.15

0.1

0.05

0
65 - 74 75 - 84 > 85
 ETIOLO
GY
TOBACCO
SMOKING
• Tobacco smoking- 20% of all cancer deaths
are attributed to smoking

•Smoking is the primary risk factor responsible

for 87% and 70% of lung cancer deaths in
males and females respectively

•Excess risk of lung cancer among continuous

smokers relative to never smokers is on the
order of 10 to 20 fold
 • Mainstream smoke-Inhalation of
air through cigarette
CARCINOGENS IN • Sidestream smoke-Smoldering of
cigarette between puffs
TOBACCO • Of the 250 known harmful
SMOKE- IARC chemicals in tobacco smoke, at
least 69 of them are carcinogenic
CLASSIFICATION
GROUP CARCINIOGENS
• Nicotine-Primary determinant of
GROUP 1- CHEMICAL IS Arsenic
CARCINOGENIC TO HUMANS Benzene
Benzo[a]pyrene
tobacco addiction
CadmiumChro
mium • Tar- Major component of lung
(Hexavalent)
Formaldehyde
4-(N-Methylnitrosoamino)-1-(3-
cancer risk
pyridyl)-1-butanone (NNK)
NickelN'-Nitrosonornicotine (NNN)
Vinyl chloride

GROUP 2A– PROBABLY Lead(Inorganic)

CARCINOGENIC

GROUP 2B- POSSIBLY Acetaldehyde

CARCINOGENIC Acrylonitrile
Isoprene
Styrene
Ever-smoker-An individual who has smoked 100 or more cigarettes during his or her lifetime.
Never-smoker-An individual who has smoked fewer than100 cigarettes during his or her lifetime.
Current smoker-An individual who is currently smoking or who has quit smoking during the past
12 months.
Former smoker-An ever-smoker who quit more than 12months earlier.
Pack year-A way to express the cumulative risk. It is calculated by multiplying the number of
packs of cigarettes smoked per day by the number of years the person has smoked.

Smoking index- Product of average numbers of cigarettes,(or bidis) smoked per day and the total
duration of smoking in years

SMOKING INDEX SEVERITY

<100 MILD

101- 300 MODERATE

>300 SEVERE
LUNG CANCER IN
NEVER SMOKERS
•An estimated 15% of lung cancers in men and
up to 53% in women worldwide occur in never
smokers, accounting for 25% of all lung cancer
cases.
•Adenocarcinoma is more common in never
smokers worldwide, followed by large cell
carcinoma, representing an undifferentiated
form of adenocarcinoma
• Possible etiologic factors
• Environmental tobacco exposure
•Environmental exposures to carcinogens due
to outdoor and indoor air pollution, exposure to
paints, thinners, solvents, welding equipments,
radon, arsenic, asbestos, arsenic, smoke
• Genetic factors
 Etiological
factors
Oncogenic viruses. Occupational carcinogens
Human papilloma virus. Asbestos
Epstein Barr virus Arsenic
Simian virus 40 Beryillium
Bk virus Cadmium
JC
virus Chromium
Cytome Nickel
galovir Silica
us Diesel
fumes
 Genetic
Host susceptibility- Two to four fold increased risk of lung cancer in persons with a positive
history of lung cancer Factors
About 85% to 90% of lung cancer risk is attributable to cigarette smoking.
However, lung cancer develops in only 15% of smokers, suggesting a differential susceptibility
to the effects of tobacco carcinogens.
 Chromosomes
involved
•Region on chromosome 6q segregates
with lung cancer in high-risk lung cancer
families.
•PARK2 has been identified as one
possible lung cancer susceptibility gene
in this region.
•Genome-wide association studies have
identified several regions associated with
lung cancer risk. These include
•chromosome 15q25-containing
CHRNA3 and CHRNA5,
• chromosome 6p21-containing
BAT3
and MSH5,
•chromosome 5p15-containing TERT
and CLPTM1L.
Classification
1. Epithelial tumors
Adenocarcinoma
Squamous cell carcinoma
Neuroendocrine tumors
Papillomas
Adenomas
2. Mesenchymal tumors
3. Lymhohistiocytic tumors
4. Tumors of ectopic origin
Germ cell tumors
Intrapulmonary thymoma
Melanoma
Menangioma, NOS
5. Metastatic tumors
CLINICAL
PRESENTATIONS
 Lymphadenopathy
Lung mass

Pleural effusion
SVC syndrome
 PARANEOPLA
STIC
•
SYNDROMES
Paraneoplastic symptoms are referred to
as effects from the cancer that are not
directly caused by invasion into vital
organs, obstruction, or space-occupying
effects from the primary cancer or
remote metastasis.
• Paraneoplastic phenomena are not
specific to lung cancer, although the
frequency of involvement is variable
among tumor types.
• Hypertrophic pulmonary
osteoarthropathy and clubbing- occur in
lung and thoracic cancers than with
other primary cancers.
• SCLC, carcinoid tumors, and other
neuroendocrine cancers- more related to
paraneoplastic phenomena than other
subtypes
 MUSCULOSKELETAL
• It is associated withMANIFESTATIONS
hypertrophic pulmonary osteoarthropathy, a condition characterized by periosteal and
subperiosteal new bone formation along the shaft of long bones and the phalanges.
• Clinically-symmetrical, painful arthropathy of the wrists, ankles, knees, and elbows.
• radiographic examination of the long bones-typical periosteal new bone formation
• Symptoms respond completely to surgical resection; however, for patients who are not surgical candidates, symptomatic
treatment includes specific systemic treatment of the cancer in addition to bisphosphonates, analgesics, including
opiates and NSAID’S
 DERMATOLOGI
CAL
•
MANIFESTATIO
Tripe palm- thickened velvety palms and pronounced
dermatoglyphics.NS
• Acanthosis nigricans- manifests as gray-brown
hyperpigmented skin plaques.
• Dermatomyositis-A typical sign of dermatomyositis is a
heliotrope rash of the upper eyelids and an erythematous rash
on the face, neck, and anterior chest (V sign) or back and
shoulders (shawl sign), knees, elbows, and malleoli. The rash
can be pruritic and may worsen after sun exposure
• Polymyositis- Presents clinically as a subacute myopathy that
evolves over weeks to months, along with weakness of the
proximal muscles.
• Dermatomyositis/Polymyositis can be the initial symptoms of
lung cancer or may develop during the course of disease
progression. Anticancer therapy may help to reduce the
symptoms otherwise, corticosteroids are the standard
treatment
 ENDOCRINE AND METABOLIC
MANIFESTATIONS
• Most endocrine paraneoplastic syndromes result from tumor secretion of peptides or hormones that result in metabolic or
homeostatic derangements
• SIADH is more common in SCLC, affecting 10% to 45% of patients,
• The hallmarks of SIADH are euvolemic hyponatremia, plasma hypoosmolality, abnormally high urinary osmolality,
and abnormally high urinary sodium concentration in the absence of confounders, such as volume depletion,
adrenal
insufficiency or hypothyroidism, and medication effects.
• The mainstay of SIADH treatment is therapy for the lung cancer, and hyponatremia may resolve within weeks from initiation
of chemotherapy for SCLC. In the interval of time before response, the hyponatremia can be managed with fluid restriction,
with or without demeclocycline or a vasopressin receptor antagonist (e.g., conivaptan or tolvaptan)
• CUSHING SYNDROME- Is due to ectopic adrenocorticotropic hormone (ACTH) secretion,and is especially seen in SCLC and
carcinoid tumors. Common symptoms include moon facies and proximal myopathy, as well as hypokalemia and
hyperglycemia. Classic features of Cushing syndrome are more likely to occur in bronchial carcinoid tumors
• Carcinoid syndrome,is the result of secretion of serotonin and other vasoactive substances released into the circulatory
system from neuroendocrine tumors. Typical carcinoid symptoms include flushing of the chest, secretory diarrhea,
bronchoconstriction, and, if the syndrome is chronic, it may lead to cardiac valvular fibrosis.
• Hypercalcemia often occurs in lung cancer and is usually a result of humoral hypercalcemia of malignancy (HHM) or
osteolytic bone metastases, is most commonly associated with squamous cell carcinoma and is caused by the production
and
secretion of parathyroid hormone (PTH)-related peptide by tumor cells. More common with squamous cell cancer
 BLOOD
• ANAEMIA DISORDERS
• LEUKOCYTOSIS

• THROMBOCYTOSIS

• HYPERCOAGULATION STATES

• DEEP VENOUS THROMBOSIS AND THROMBOEMBOLISM

• DISSEMINATED INTRAVASCULAR COAGULOPATHY

• THROMBOTIC MICROANGIOPATHY
 Paraneoplastic neurologic syndromes
• Rare,affecting approximately 0.01% of patients with cancer overall, but
they are more frequently found in patients with SCLC (3–5%)
• Due to immune crossreactivity between cancer cells and antigens of the
nervous system
• Because the tumor cells do not directly produce the syndrome, treatment of
the primary cancer may not always abolish the syndrome and additional
immunosuppressive therapy is often required.
CENTRAL NERVOUS SYSTEM PERIPHERAL NERVOUS SYSTEM NEUROMUSCULAR GROUP OF
PNS
Limbic encephalitis Sensory neuropathy Lambert Eaton myasthenic
syndrome
Subacute cerebellar Autonomic neuropathy
degeneration
Encephalomyelitis Opsoclonus-myoclonus
SUPERIOR VENACAVA
• The superior vena cava (SVC) is a large
SYNDROME
valveless venous channel formed by the union of
the brachiocephalic It receives blood from the
head, neck and upper extremities and returns it to
the right atrium

• Significant extrinsic pressure, encasement,

thrombosis, or actual invasion of the superior
vena cava may cause an obstruction of the venous
return from the head, neck, and upper
extremities, leading to signs and symptoms due to
obstruction termed as “superior vena cava
syndrome
 ETIOLO
• Majority of SVC syndromes GY
are the result of mediastinal malignancies,
primary among which is SCLC

• The second most commonly associated malignancy is non-Hodgkins

lymphoma, followed by metastatic tumors

• Benign causes include

• granulomatous mediastinitis, mediastinal fibrosis, intrathoracic goiter or
aneurysm, placement of pacemakers or thrombosis complicating central
venous catheterization
 MECHANISMS OF SVC
• Extrinsic compression and obstruction of the SVC by a mass in the
OBSTRUCTION
mediastinum is the most common cause of SVC syndrome, and is most often
caused by malignancy

• Occlusive venous thrombus formation that compromises venous flow back to

the heart. The increasing use of indwelling intravascular devices such as
catheters as well as pacemakers and implantable cardioverter defibrillator
(ICD) leads have played a major role in this growth

• These mechanisms often coexist in patients presenting with SVC syndrome.

• Symptoms of SVC syndrome are often debilitating,
tend to get exacerbated in supine position, include
• progressive swelling of neck, face, eyelids, arms and upper
chest
• conjunctival congestion,
• epistaxis, tinnitus,
• Headache
• disturbances in vision and sensorium
• Neck veins are distended and nonpulsatile,
well developed collaterals are usually obvious on
neck and anterior chest wall.
• SVC obstruction may get complicated with jugular
venous and cerebrovascular thrombosis.
• The phrenic, vagus, and sympathetic nerves all lie
within the superior mediastinum; involvement of
these structures can lead to paralysis of the right
hemidiaphragm, hoarseness, pain, or Horner’s
syndrome and pemberton’s sign can be seen
Investigations for Lung Cancer
CHEST X-
RAY
Role of CT CHEST IN DIAGNOSIS
Mass
Pleural
Effusion
MEDIASTINAL LYMPH
NODES
BRONCHIAL CUT
OFF
Role of MRI in
diagnosis
 Pancoast Tumour and syndrome

• The formal definition of Pancoast tumor, as provided by the

American College of Chest Physicians (ACCP) , is: “a lung cancer
arising in the apex of the lung that involves structures of the apical
chest wall. Invasion of apical chest wall structures is required at the
level of the first rib or above, but it is not necessary to have Horner
syndrome or pain radiating down the arm. These lesions frequently
invade the brachial plexus, subclavian vessels, or spine.”
The Pancoast-Tobías syndrome is characterized by one or more of the
following symptoms …

1.Severe shoulder pain that aggravates over time. The pain may radiate
to the neck, to the axilla, to the anterior chest wall, to the medial
aspect of the arm and forearm as far as the wrist, along with the
distribution of the ulnar nerve (C8–T1 nerve roots). The pain is
provoked by the invasion of the chest wall and brachial plexus;
2.Claude-Bernard-Horner syndrome (ptosis, miosis, enophthalmos and
anhidrosis of the ipsilateral side of face), related to invasion of the
sympathetic chain and of the inferior cervical (stellate) ganglion;
3.Weakness and muscle atrophy of the intrinsic muscles of the hand,
indicative of tumor infiltration of the ulnar nerve;
4.Upper arm edema, in case of invasion and partial or complete
occlusion of the subclavian vein.
 Primarily a metabolic
PET And has limited anatomical resolution
examination

SCAN Provides information about

Primary tumour, mediastinal
Lymph nodes, and distant
Metastasis

Useful in assessing prognosis to

Treatment and selection of site for biopsy
SAMPLING OF PRIMARY
TUMOUR
MEDIASTIN
AL LYMPH
NODES
MEDIASTINAL LYMPH
NODE
ACCESSIBILITY
TNM
STAGING
PREOPERATIVE SURGICAL
EVALUATION MANAGEME
NT
For stage I and II non
small cell lung cancer,
resection is the best
validated treatment
option with aim for
cure, for which not only
should the tumor be
resectable, but also the
patient should be fit
enough to undergo
resection as well as to
have satisfactory
postoperative quality of
life
 SURGICAL
OPTIONS
LOBECTOMY- Tumors located within the centre of the lobe or near the hilum typically
require lobectomy, it is an anatomical resection that removes the regional lymph nodes
located along the lobar bronchus

LIMITED RESECTION-WEDGE RESECTION AND SEGMENTECTOMY

Only in patients with clinical stage I cancer(T1N0,T2N0)
Segmentectomy is a favourable option than wedge resection as it provides a wider
parenchyma margin, encompasses regional Lymphatics and lymph nodes to be evaluated
during resection

PNEUMONECTOMY AND EXTENDED RESECTIONS

Pneumonectomy is indicated when there is proximal involvement of the main pulmonary
artery, extensive endobronchial involvement, involvement of confluence of pulmonary
veins or left atrium
Sleeve resections are technically more demanding procedures that result in same
bronchial resection as pneumonectomy yet preserving the lung tissue
 LYMPH NODE SAMPLING
Pulmonary resection is incomplete without excision of lymph nodes to complete the
staging assessment
In some situations, frozen section on N1 nodes during segmentectomy is done and if
positive for cancer, the operation is converted to lobectomy
Accurate staging through appropriate lymph node harvest improves prognostic accuracy
and determines the patients to be taken for adjuvant treatment
CHEST WALL RESECTION
5% of lung cancers involve chest wall by direct extension, it is important to rule out
disseminated disease before considering surgery in a patient with chest wall involvement
Mediastinal lymph node involvement is the single best prognostic indicator in these
patients
TUMORS OF SUPERIOR SULCUS
The presence of N2 disease remains a contraindication to surgery.Typical treatment
include
induction chemoradiation followed by resection and planned follow up chemotherapy
 RADIATION
THERAPY FOR
NSCLC
• Categories include,
• Neoadjuvant- Preoperative
• Adjuvant-Postoperative
• Definitive-cure without surgery as treatment goal
with or without chemotherapy
• Palliative-Directed at relief of thoracic symptoms
 CHEMOTHERAPY IN
NSCLC
•Systemic therapy remains the
principal therapeutic modality for
advanced NSCLC
•The determination of tumour
histology has become essential in
decision making
•Platinum doublet therapy is the
established standard first line
therapy in patients with advanced
or metastatic NSCLC
•For patients with tumor PDL-1
expression >50%,
pembrolizumab, an immune
checkpoint inhibitor is superior to
platinum based therapy
•Patients with activating
mutations in EGFR benefit from
upfront therapy with EGFR
tyrosine kinase inhibitors and
patients with ALK rearrangements
can be treated with ALK inhibitors
such as crizotinib
 •Platinum compounds form DNA addicts,which ultimately result in
PLATINUM activation of p53 dependant and p53 independent apoptosis
•Combination of cisplatin with third generation drugs seem to exert
COMPOUN higher efficacy and improved tolerability

DS •The choice of newer agent (gemcitabine,paclitaxel or vinorelbine)

combined with cisplatin does not seem to significantly affect the
treatment efficacy
•In clinical studies, non haematological tolerability of carboplatin is
superior to that of cisplatin, making it more convenient platinum analog
for palliative therapy
 ANTI ANGIOGENIC
THERAPY
The monoclonal anti-VEGF antibody bevacizumab,which blocks the binding of VEGF to its high
affinity receptors, is currently the only anti angiogenesis agent approved for treatment of lung
cancer
Massive pulmonary haemorrhage as a complication is associated with squamous cell
tumours,cavitation and bronchial tumours, hence it is not used in those instances
 MOLECULAR TARGETED
The identification of driver mutations, those mutations that drive neoplastic transformation
THERAPY
to tumor progression has provided two clinically important targets
Epidermal growth factor receptor mutation
EML-4-ALK translocation
The presence of driver mutations allows targetting of mutant
proteins that are present only in
lung cancer avoiding systemic toxicity seen in non targeted therapy
Most EGFR mutations are in the tyrosine kinase domain and result in activation of EGFR and
unregulated signalling, thus forming the basis of use of Erlotinib and Geftinib, EGFR tyrosine
kinase inhibitors as a treatment for lung cancer.
EGFR mutations are more significant in women and non smokers

The EML4-ALK translocation in NSCLC leads to consecutive activation of ALK domain and
promotes cell growth and survival
Seen in never smokers or light smokers with adenocarcinomas.
Crizotinib, a TKI is an approved drug that has shown increased rates of disease control in
patients with lung cancer with EML4-ALK translocation
 MAINTANENCE
THERAPY
Offers the possibility of continued active treatment to delay disease progression and
improved overall survival in patients with advanced NSCLC, already treated with induction
chemotherapy
Target population-patients who achieved objective response/disease stabilisation with
induction chemotherapy with minimal cumulative toxicity

As a result of this trial, pemetrexed was approved as switch maintanence therapy for
metastatic NSCLC,specifically for patients with non squamous cell tumours in whom disease
has not progressed with first line platinum based therapy
 TREATMENT OF SMALL CELL LUNG
CANCER

As first line therapy, platinum agents plus etopside or irinotecan

remains the standard of care for SCLC

Despite an initially high response rate to frontline platinum based

chemotherapy,extensive stage SCLC will universally relapse within 3 to
6 months
 SECOND LINE
CHEMOTHERAPY

The topoisomerase inhibitor Topotecan represents a reasonable standard of care for

patients relapsed with SCLC
 RADIOTHERAPY IN SMALL CELL
CARCINOMA
NON METASTATIC/LOCALISED DISEASE

In patients with non metastatic SCLC or Localised disease, combined chemoradiation is the
standard line of treatment
Concomitant chemoradiotherapy dives the best results and is preferential to sequential
radiotherapy
In those who achieve a complete or partial response to initial therapy, Prophylactic cranial
irradiation(PCI) at a dose of 25Gy in 10 daily fractions is recommended. It should not be
administered concomitantly with chemotherapy
EXTENSIVE DISEASE
The hypothesis to add RT to chemotherapy is based on possible improvement in local control
and survival benefits by controlling residual disease that is resistant to chemotherapy.
The role of radiation therapy in extensive SCLC was traditionally reserved for patients who
required local palliation, and typically was not considered part of the standard of care
In metastatic SCLC, PCI is also recommended among patients with any response to
chemotherapy. The same regimen (25 Gy/10 fractions per 2 weeks) or a more
hypofractionated regimen (20 Gy/5 fractions per 1 week) may be administered
DIFFERENTIAL
DIAGNOSIS OF
LUNG CANCER

• The differential diagnosis of

lung cancer includes a
variety of infectious and
non infectious benign
conditions which has to be
differentiated from
malignancy by means of
clinical and
pathological features
 LUNG
CANCER
SCREENING
•Pulmonary nodules are frequently
encountered incidentally on chest CT.
•Pulmonary nodules can be divided into
solid lesions and subsolid lesions, which
can be further subdivided into part-solid
and pure ground glass nodules
• Subsolid nodule (SSN)
A pulmonary nodule with at least partial
groundglass appearance
• Groundglass
Opacification with a higher density than
the surrounding tissue, not obscuring
underlying bronchovascular structures
UP
OF
DUL
ES
 FOLLOW UP OF
SSN
•Most subsolid nodules are transient
and the result of infection or
hemorrhage.
However, persistent subsolid nodules
often represent pathology in the
adenocarcinomatous spectrum.

•Compared to solid lesions,

persistent subsolid nodules have a
much slower growth rate, but carry a
much higher risk of malignancy.
In a study by Henschke et al.,
•part-solid nodules were malignant
in 63%
• pure groundglass SSNs in 18% and
• solid nodules only in 7%
Dedicatio
n

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