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LUNG CANCER
Dr. Başak Oyan-Uluç
Yeditepe University Hospital
Department of Medical Oncology
Lung Cancer
• Uncontrolled growth of malignant cells in
one or both lungs and tracheo-bronchial tree
• A result of repeated carcinogenic irritation
causing increased rates of cell replication
• Proliferation of abnormal cells leads to
hyperplasia, dysplasia or carcinoma in situ
Epidemiology
• Second most common tumor
• 1st cause of cancer deaths
• In USA: Decreasing incidence and deaths in
men; continued increase in women
• Women are more prone to tobacco effects
1.5 times more likely to develop lung
cancer than men with same smoking
habits
Etiology
• Smoking
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Cause of 90% of lung cancers
Increase risk 30 times
Cumulative dose important (pack-years)
Cigars, pipes: increase risk 2 times
Chewing tobacco
>20 packs-year: 1/7 die from lung cancer
Incidence diverge from nonsmoking population at 10 packs-year.
Passive smoking: increases risk 2 fold, cause in 17% of lung
cancers in non-smokers
– Other tumors caused by smoking: Oral cavity, esophagus, larynx,
bladder, renal, pancreas, cervical
•
Radiation exposure:
– Increase risk of small cell lung cancer (SCLC)
– Radon: assosiated with 6% of lung cancer
Etiology
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Asbestos:
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crocidolite and amosite: Most carcinogenic
Risk: 3-4x
Isolation, pipe fitters, mining
Asbestos and smoking: synergistic, risk 80-90x
•
Other substances: Arsenic, nickel, chromium, chlomethyl ether, air
pollutants
•
Lung cancer:
– Increased risk of a second lung cancer
– Other cancers of upper aerodigestive tract also increased FIELD
CANCERIZATION
•
Other lung diseases
– Lung scars: tuberculosis, Scleroderma- bronchoalveolar cancer
•
Genetic factors:
– High metabolizers of debrisoquine
– Lack of µ class phenotype of glutathione transferase
Smoking Facts
• Risk related to:
– age of smoking onset
– amount smoked
– gender
– product smoked
– depth of inhalation
Pathology
• Small cell lung cancer (SCLC) (15%)
– 95% central or hilar
– Widespread disease at diagnosis
– Hematogenous metastasis: brain, bone
marrow, liver
– Pleural effusions common
Pathology
• Non-small cell lung cancer (NSCLC) (85%)
– Adenocarcinoma (50-60 % of NSCLC)
• Most common cell type occurring in non-smokers
• Spread widely outside thorax by hematogenous dissemination
• Bronchoalveolar carcinoma:
– Spreading pattern within bronchioles without evidence of invasion
– Radiology: Infiltrative, frequently multicentric
– More frequently in young, female nonsmokers
– Squamous cell (20-25% of NSCLC)
• Central location
• Most likely to be localized early in disease
– Large cell
– Mix type
Uncommon tumors of the lung
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Bronchial carcinoids
Cystic adenoid carcinomas
Carcinosarcomas
Mesotheliomas
– Caused by exposure of asbestosis
– Occur in lung, pleura, peritoneum, tunica
vaginalis or albeuginea of testis
– Spreads rapidly over pleura, encases lung
parenchyma
Where does it spread?
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Lymph Nodes
Brain
Bones
Liver
Lung/Pleura
Adrenal Gland
• 40% of metastasis occurs in the
Adrenal Gland
Symptoms
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Cough
Dyspnea
Hemoptysis
Recurrent infections
Chest pain
• Symptoms related to distant metastases
– Pain
– Organ-related
• General Symptoms
– Weight loss
– Fatigue
Syndromes/Symptoms secondary to
regional metastases
• Esophageal compression  Dysphagia
• Laryngeal nerve paralysis  Hoarseness
• Symptomatic nerve paralysis  Horner’s syndrome
• Cervical/thoracic nerve invasion  Pancoast syndrome
• Lymphatic obstruction  Pleural effusion
• Vascular obstruction  SVC syndrome
• Pericardial/cardiac extension  Effusion, tamponade
Sympathetic pathway for pupillary innervation
Horner’s syndrome
Ptosis
Miosis
Anhidrosis
In dim light, the anisocoria is accentuated with the right
pupil more miotic. The right upper lid is ptotic by 1.5 mm.
Diagnosis
• History and Physical exam
• Diagnostic tests
– Chest x-ray
– Pathological evaluation by:
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Sputum cytology
Flexible fiberoptic bronchoscopy
Percutanous and transbronchial needle biopsy
Lymph node metastases
• Staging tests
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CT chest/abdomen
Bone scan
Bone marrow aspiration
PET scan
Bronchoscopy
Bronchoscopy
Biopsy
Solitary pulmonary nodule (SPN)
• A lesion that is both within and surrounded
by pulmonary parenchyma
• Size: < 3-4 cm
• The major question that follows detection
of a SPN: Whether the lesion may be
malignant?
Evaluation of solitary pulmonary nodule
Diagnostic strategy:
1. Maximize chance of detecting cancer
2. Minimize chance of performing a unnecessary
thoracotomy if the nodule is benign
Characteristics that define a solitary pulmonary
nodule
1.
2.
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A peripheral lung mass <3-4 cm
Asymptomatic
Physical examination: normal
CBC, LFT: normal
Likelihood that a nodule is malignant
- Clinical Features • Age: Risk increases with age
<35 years
35-39 years
40-49 years
50-59 years
≥ 60 years
• Smoking history
2%
3%
15%
43%
≥50%
Likelihood that a nodule is malignant
- Radiographic Features •
Size (risk increases with size)
< 3 mm
4-7 mm
8-20 mm
>20 mm
•
0.2%
0.9%
18%
50%
Border
Growth (Volume doubling time)
<20 days
20-400 days
>400 days
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<1%
30-50%
<1%
Ground glass appearance
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– Malignant: <147 Hounsfield
units (HU)
– Benign: >167 HU
• Calcification
Malignant: More irregular and
spiculated borders
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• Density
Frequently malignant (40-60%)
– Eccentric: carcinoma arising
in an old granulomatous
lesion (ie, a "scar"
carcinoma)
– Benign calcifications
• “Popcorn" calcification
• Laminated (concentric)
calcification
• Central calcification
• Diffuse, homogeneous
calcification
Evaluation of solitary pulmonary nodule
• Serial CT scans
• Metabolic imaging (PET/CT)
• Nodule sampling
– Bronchoscopy
– Percutaneous needle aspiration
SPN algorithm
Management of lung cancer
1. Accurate diagnosis
a. SCLC
b. NSCLC
2. Staging
3. Selection of treatment modality
Staging
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Bone scan
Spinal MRI
Brain CT or MRI
Mediastinoscopy
PET, PET/CT
Bone marrow aspiration and biopsy
NSCLC
• 80% of all lung cancers are NSCLC
• Survival is improved when found at an
early stage
• Three distinct types of NSCLC
• Treatments are the same
Staging and Treatment of
NSCLC-Simplified
NSCLC
Stage I
 2 cm
T1
Ia
N0
M0
T2
Ib
N0
M0
Any of the following:
T > 3 cm
T  3 cm
No lobar
bronchus
involvement
N0: no lymph node involvement
M0: no distant metastasis
T= main bronchial
involvement
 2 cm distal to carina
T + visceral pleural
involvement
T + distal atelectasis
NSCLC
 2 cm
Stage II
IIa
T1
N1
M0
T2
IIb
N1
M0
T3
N0
M0
Any of the following:
T+ main bronchial
involvement < 2 cm distal
to carina
T (any size) invading
chest wall,
diaphragm,
mediastinal pleura,
or pericardium
T + total atelectasis
N1: ipsilateral peribronchial and/or ipsilateral hilar nodes involved
M0: no distant metastasis
NSCLC
<2 cm
 2 cm
Stage IIIa
T3
T3
N1
N2
M0
M0
T2
T1
T2
N2
N2
M0
M0
T  3 cm
OR
T  chest wall
(or diaphragm)
OR
T + visceral
pleura involved
OR
T  mediastinal pleura
(or pericardium)
OR
T + atelectasis
T  3 cm
No lobar-bronchus involvement
N1: ipsilateral peribronchial and/or ipsilateral hilar nodes involved
N2: ipsilateral mediastinal and/or subcarinal nodes involved
M0: no distant metastasis
NSCLC - Stages at Presentation
7%
Stage II
31%
Stage III
24%
Stage I
38%
Stage IV
Fry WA, et al. Cancer. 1996;77:1949-1995.
Management of NSCLC
• Staging to determine resectability (tumor can
be surgically removed with clear margins)
• Patient evaluation for operability (patient is
capable of withstanding such a procedure)
Management of NSCLC
• Surgery: Mainstay of treatment
– Primary mode of therapy in stage I and II
– Resectability: determined by extent of tumor
– Operability: Overall medical condition of patient
– ½ of NSCLC patients: operable
– ½ of tumors in operable patients are resectable (25%
of all patients)
– ½ of patients with resectable tumors survive 5 years
(12% of all patients, 25% of operable patients)
Determinants of resectable disease:
Signs of unresectable NSCLC
• Distant metastases, including metastases to opposite lung
• Persistant pleural effussions with malignant cells
– Cytological examination: positive for malgnant cells in 65%
• Superior vena cava obstruction
• Involvement of following structures:
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Supraclavicular and neck lymph nodes (N3)
Contralateral mediastinal lymph nodes (N2)
Recurrent laryngel nerve
Tracheal wall
Main stem bronchus <2 cm from carina (resectable by sleeve
resection technique)
Determinants of operability: Signs of
inoperability
• Age and mental status: not factors
• Cardiac status
– Uncontrolled cardiac failure
– Uncontrolled arrhytmia
– Recent myocardial infarction (within 6 months)
• Pulmonary status: the patients ability to tolerate
resection of part of or all of a lung must be
determined
– Pulmonary hypertension
– Inadequate pulmonary reserve
Prognosis
• TNM staging
• Performance status
• Weight loss
• Tumor histology: not influence prognosis
• Molecular prognostic factors
– Supressor oncogene alterations: poor prognosis
– Mutated p53: 50% in NSCLC, in almost all with
SCLC
– Dominant oncogene overexpression (c-mys, kras, erb-B2): poor prognosis
Survival
Stage
I
II
IIIa
IIIb
IV
5-year Survival
60-80%
40-50%
25-30%
5-10%
<1%
SCLC
• Most aggressive type of lung cancer
• Responds to chemotherapy and
radiation
• Recurrence rates are high
Staging of SCLC
• Limited Stage
Tumor is in one lung, the mediastinum and lymph nodes
that can be radiated using a single radiation port.
• Extensive Stage
Tumor has spread beyond one lung, the mediastinum
and local lymph nodes.
Common distant sites of metastases are the
adrenals, bone, liver, bone marrow, and brain.
Management of SCLC
Limited stage:
• Radiotherapy and concomitant chemotherapy
• Prophylactic brain irradiation
• Rarely: Surgery
• <5%: Stage I, II
• 30%: stage IIIA, IIIB
Extensive stage: Chemotherapy
SCLC: Survival
• Limited Disease:
– Median survival 18-20 months
– 5-year survival 10%
• Extensive Disease:
– Median survival 10-12 months
– 5-year survival 1-2%
Complications
• Treatment related:
– Chemotherapy
– Radiotherapy
– Infection
• Disease related
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Superior vena cava syndrome
Brain metastasis
Carcinomatosis leptomeningitis
Paraneoplastic syndromes
What are Paraneoplastic Syndromes?
• Heterogeneous group of disorders
• Cause symptoms independent of:
– Tumor invasion/metastasis
– Infection
– Ischemia
– Metabolic/nutritional deficits
– Tumor treatment
Mechanism
Paraneoplastic Syndromes
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Cancer cachexia
Fatigue
Electrolyte dysfunction
Endocrine dysfunction
Neurological dysfunction*
Cutaneous lesions*
Hematological dysfunction
Coagulation dysfunction
Fever
Hepatic dysfunction
Renal dysfunction
Most common paraneoplastic syndromes
in lung cancer-1
• Hypercalcemia
– Mostly in squamous cell carcinoma
• Hypertrophic osteoartropathy
– Clubbing + periosteal proliferation of tubular bones
– Associated with lung cancer and other lung disease
– Clinically:
• Symmetrical painful arthropathy
• Usually involves ankles, wrists and elbows
• Metacarpal, metatarsal and phalangeal bones may also be
involved
– Tx: If inoperable tm  NSAID, bisphosphonates
Hypertrophic osteoartropathy
A) Side and B) top view of nail bed hypertrophy causing
a distal enlargement of the fingers in a patient with lung
cancer.
Hypertrophic osteoartropathy
Bone scan showing diffuse uptake
by the long bones in a patient
with painful arthropathy and
lung cancer.
Normal bone scan for comparison
Most common paraneoplastic syndromes
in lung cancer-2
• SIADH secretion
– Mostly in SCLC
– 10% of SCLC have SIADH
– SCLC accounts for 75% of all malignancy
associated SIADH
• Cushing syndrome
– Ectopic secretion of ACTH
– Most common in SCLC and carcinoid tumors of
lung and extrathoracic malignancies
– If present, prognosis worse
Most common paraneoplastic syndromes
in lung cancer-3
• Hematologic
– Anemia
– Leukocytosis
• Due to overproduction of G-CSF (Granulocyte-colony stimulating
factor
• Nearly all in NSCLC
– Thrombocytosis
– Eosinophilia
• In large cell carcinoma
– Hypercoagulable disorders
• Trousseau’s syndrome (migratory superficial thrombophlebitis)
• Deep vein thrombosis and thromboembolism
• Disseminated intravascular coagulopathy
Most common paraneoplastic syndromes
in lung cancer-4
• Neurologic
– Lung cancer is the most common cancer associated with
paraneoplastic neurological syndromes
– Typically associated with SCLC
– Immune-mediated
– Lambert Eaton myasthenic syndrome
• Most in SCLC
• In >80%: precede diagnosis of SCLC often by months to years
Cerebellar ataxia
Sensory neuropathy
Limbic encephalitis
Autonomic neuropathy
Retinopathy
Opsoclonus
– Generally not improve with immunosuppressive treatment
Most common paraneoplastic syndromes
in lung cancer-5
• Dermatomyositis and polymyositis
– Inflammatory myopathy
– Clinically muscle weakness
– Presenting symptom or develop later in the course of
disease
– In lung cancer, also in ovary, cervix, pancreas, bladder,
stomach
Targeted Therapies in NSCLC
• EGFR Inhibitors
– Gefitinib (Iressa)
– Erlotinib (Tarceva)
• EGFR Monoclonal antibodies
– Cetuximab (Erbitux)
• VEGF Monoclonal antibodies
– Bevacizumab (Avastin, Altuzan)
Targeted Therapies
Bevacizumab
Cetuximab
Erlotinib
Gefitinib
PI3K
Chemotherapy
Inhibition of
programmed cell
death (apoptosis)
Tumor cell
proliferation
Tumor cell
invasion
metastasis
Development of
tumor vasculature
(angiogenesis)
Conclusion
• Lung cancer is the leading cause of cancer
deaths.
• Only prevention: Not smoking
• Most diagnosed at advanced stage
• Overall 5-year survival rate: 15%
• Treatment depends on histology and stage