2. INTRODUCTION
Lung cancer is largely a disease of modern man.
Rare before 1900, with fewer than 400 cases
described in the medical literature.
Raymond Pearl's landmark 1938 report conclusively
established the devastating impact smoking has on
longevity.
: Abeloff's Clinical Oncology, 4th ed.
3. Tobacco consumption is the primary cause of
lung cancer.
More than 60% of new lung cancers occur in
- Never smokers (smoked <100 cigarettes per lifetime) or
- Former smoker (smoked 100 cigarettes per lifetime, quit
1 year)
1 in 5 women and 1 in 12 men diagnosed with
lung cancer have never smoked.
: Abeloff's Clinical Oncology, 4th ed
4. Epidemiology
Lung cancer is the most common cause of cancer
death among American men and women.
More than 220,000 individuals will be diagnosed with
lung cancer in the United States in 2010.
Lung cancer is rare below age 40, with rates increasing
until age 80, after which the rate tapers off.
Harrison's Principles of Internal Medicine, 18e
5. The projected lifetime probability of
developing lung cancer is estimated to be
approximately 8% among males and
approximately 6% among females.
The incidence of lung cancer varies by racial
and ethnic group, with the highest ageadjusted incidence rates among African Americans.
: Abeloff's Clinical Oncology, 4th ed
6. Demographic data of lung cancer from Indian studies.
S. No
Details
1958 – 1985
1986 - 2001
1.
Total cases
1735
2973
2.
M:F
6.67:1
5.76:1
3.
Mean age (yrs)
52.16
54.6
4.
Urban: Rural
19.6 - 81.6
18.4 - 80.4
5.
Occupation
Farmers
Labourers
Clerks/teachers
Businessmen
Housewives
Others
13.9 - 48%
21.0 - 27.3%
16.7%
21.3%
8.0 - 14.7%
23%
6.
Religion
Hindus
Muslims
Christians
75.1%
18.9%
5.9%
:IACM Journal April-June 2012
7. Lung cancer incidence in United States between 1975 and 2003. Age-adjusted to the
2000 U.S. standard population
: Abeloff's Clinical Oncology, 4th ed
8. Tobacco use and lung cancer mortality in the United States 1900–2002.
*Per 100,000, age-adjusted to the 2000 U.S. standard population
: Abeloff's Clinical Oncology, 4th ed
9. Age-adjusted cancer death rates for selected sites in the United States, adjusted for the 2000
ROBBINS AND COTRAN PATHOLOGIC BASIS OF DISEASE, 7/E
10. RISK FACTORS
Majority (80–90%) by cigarette smoking.
-Cigarette smokers have a tenfold or greater increase in
risk.
-One genetic mutation is induced for every 15 cigarettes
smoked.
- Cigarette smoking increases the risk of all the major
lung cancer cell types.
- Environmental tobacco smoke (ETS) or secondhand
smoke is also an established cause of lung cancer.
Harrison's Principles of Internal Medicine, 18e
11. In Indian patients with lung cancer, history of active
tobacco smoking was found in 87% of males and 85% of
females.
History of passive tobacco exposure is found in 3% in
india. So 90% of all cases in india resulted from tobacco
exposure.
The relative risk of developing lung cancer is
2.64 for beedi smokers
2.23 for cigarette smokers
2.45 as the overall relative risk (RR).
IACM Journal April-June 2012
12. Occupational risk of lung cancer:
S.No
Occupational
carcinogens
Risk
1.
Asbestos
Insulation and shipyard workers,increase in
risk of lung cancer after 10 years of exposure,
with concurrent smoking increases risk 90
fold.
2.
Arsenic
Smelters and vineyard workers,
Upper lobe predominance.
3.
Nickel
Squamous cell carcinoma-MC
4.
Radiation
Uranium mining, Oat cell carcinoma -MC
5.
Haematite mining
Due to radon exposure
6.
Hard rock mining
Chromium exposure,Squamous cell- MC
7.
Chloromethyl
Oat cell -MC
8.
Ethers and mustard
gas
Squamous and undifferentiated -MC
9.
Soots , Tars
Coke oven workers
10
Oils and cokes
Gas house workers, roofers
:IACM Journal April-June 2012
13. Low fruit and vegetable intake during adulthood.
-This observation led to hypotheses that specific
nutrients, in
particular retinoids and carotenoids, might have
chemopreventive effects for lung cancer.
Ionizing radiation
-Increased rates of lung cancer among survivors of the
atom bombs dropped on Hiroshima and Nagasaki
Prolonged exposure to low-level radon in homes
Harrison's Principles of Internal Medicine, 18e
14. Prior lung diseases such as
-chronic bronchitis,
-emphysema, and
- tuberculosis
Air pollution:
Studies from china have shown :
- Coal burning at home is a significant risk factor
for development of lung cancer in non smoking females.
- Coal smoke contains potential carcinogens:
SO2 ,CO , TSP , B(a)P, radon , thoron.
:IACM Journal April-June 2012
15. SMOKING CESSATION
Physicians must promote tobacco abstinence.
Stopping tobacco use before middle age avoids
more than 90% of the lung cancer risk attributable
to tobacco.
Smoking cessation is beneficial in individuals
even with an established diagnosis of lung cancer.
Harrison's Principles of Internal Medicine, 18e
16. Essential elements of smoking cessation
therapy:
The individual must want to stop smoking.
Must be willing to work hard to achieve the goal of
smoking abstinence.
Therapy with :
-an antidepressant (e.g., bupropion) or
- nicotine replacement therapy (varenicline).
- Clonidine and nortriptyline are recommended as secondline treatments
Harrison's Principles of Internal Medicine, 18e
17. Inherited Predisposition to Lung
Cancer
Environmental carcinogens can induce or facilitate the
transformation from bronchoepithelial cells to the
malignant phenotype.
Certain genetic polymorphisms of the P450 enzyme
system, specifically CYP1A1, or chromosome fragility are
associated with the development of lung cancer.
Harrison's Principles of Internal Medicine, 18e
18. First-degree relatives of lung cancer probands have a two- to
threefold excess risk of lung cancer and other cancers, many
of which are not smoking-related.
Individuals with inherited mutations in RB
(retinoblastoma) and p53 (Li-Fraumeni syndrome)
genes may develop lung cancer.
Harrison's Principles of Internal Medicine, 18e
19.
Three genetic loci for lung cancer risk have been
identified :
-5p15 (TERT-CLPTM1L),
-15q25(CHRNA5-CHRNA-3 nicotinic acetylcholine
receptor subunits), and
-6p21 (BAT3-MSH5).
A rare germline mutation (T790M) involving the
epidermal growth factor receptor (EGFR) maybe be linked
to lung cancer susceptibility in never smokers.
Harrison's Principles of Internal Medicine, 18e
20. Pathology
The term lung cancer is used for tumors
arising from the respiratory epithelium
(bronchi, bronchioles, and alveoli).
Harrison's Principles of Internal Medicine, 18e
21. 2004 World Health Organization Classification of
Malignant Epithelial Tumors
Squamous cell carcinoma
Papillary
Clear cell
Small cell
Basaloid
Small cell carcinoma
Combined small cell carcinoma
Adenocarcinoma
Mixed pattern
Acinar
Papillary
Bronchioloalveolar
Mucinous
:Fishman’s Pulmonary Diseases and Disorders
Nonmucinous
22. Mixed
Solid with mucin production
Fetal adenocarcinoma
Mucinous (colloid) carcinoma
Mucinous cystadenocarcinoma
Signet ring
Clear cell
Large cell carcinoma
Large cell neuroendocrine carcinoma
Basaloid carcinoma
Lymphoepithelioma-like carcinoma
Clear cell carcinoma
Large cell carcinoma, rhabdoid phenotype
:Fishman’s Pulmonary Diseases and Disorders 4th Edition
24. These four histologies account for approximately
90% of all epithelial lung cancers.
1.Small Cell Lung Cancer (SCLC)
2.Adenocarcinoma
3.Squamous Cell Carcinoma
Non Small Cell Lung
Cancer(NSCLC)
4.Large Cell Carcinoma
:Harrison's Principles of Internal Medicine, 18e
25. Epithelial cell lung cancers
WESTERN COUNTRIES
Squamous
Large
INDIA-1986-2001
Others
Adeno
Small
:Harrison's Principles of Internal Medicine, 18e
Squamous
Large
Adeno
:IACM Journal April-June 2012
26. Among women and young adults (<60 years),
adenocarcinoma tends also to be the most common
form of lung cancer.
In lifetime never smokers, all histologic forms of
lung cancer can be found, although adenocarcinoma
tends to predominate.
The incidence of small cell carcinoma is also on the
decline.
:Harrison's Principles of Internal Medicine, 18e
27. LUNG CANCER IN INDIA
Non-small-cell lung cancer constitutes 75 - 80% of lung cancers.
More than 70 % of them are in Stages III and IV, thus
curative surgery can not be done in these cases.
Small-cell lung carcinoma constitute 20% of all lung cancers .
Extensive stage in 70% of patients at the time of diagnosis.
While in many Western countries adenocarcinoma has become
the commonest lung cancer.
In India it is still squamous cell carcinoma in both males and
females
:IACM Journal April-June 2012
28. Small cell carcinoma
Poorly differentiated
neuroendocrine tumor.
Highly prevalent in smokers.
Incidence rates are higher among men than women.
Central mass with endobronchial growth.
:Abeloff's Clinical Oncology, 4th ed
29. May produce specific peptide hormones such as
- adrenocorticotrophic hormone (ACTH),
- arginine vasopressin (AVP),
-atrial natriuretic factor (ANF), and
-gastrin-releasing peptide (GRP).
These hormones may be associated with distinctive
paraneoplastic syndromes
:Abeloff's Clinical Oncology, 4th ed
31. Small cell carcinoma with islands of small deeply
basophilic cells and areas of necrosis
:ROBBINS AND COTRAN PATHOLOGIC BASIS OF
DISEASE, 7/E
32. A fine-needle aspirate of an enlarged lymph node shows clusters of tumor
cells from a small cell carcinoma, with molding and nuclear atypia
characteristic of this tumor
:ROBBINS AND COTRAN PATHOLOGIC BASIS
OF DISEASE, 7/E
33. Squamous cell carcinomas
Identical to extrapulmonary (i.e., head and neck)
squamous cell carcinomas .
Occur centrally .
Classically associated with a history of smoking.
Pattern is that of an infiltrating nest of tumor cells with
central necrosis , resulting in cavitation.
:Abeloff's Clinical Oncology, 4th ed
34. Keratin can usually be seen when present.
Important variants-papillary pattern
-basaloid variant
Differential diagnosis
-reactive processes that may result in squamous
metaplasia with reactive atypia such as that
observed with infection or radiation-induced injury.
:Abeloff's Clinical Oncology, 4th ed
36. Cavitation within a squamous cell carcinoma.
:Fishman’s Pulmonary Diseases and Disorders 4th Edition
37. A sputum specimen shows an orange-staining, keratinized squamous
carcinoma cell with a prominent hyperchromatic
nucleus (arrow)
:ROBBINS AND COTRAN PATHOLOGIC BASIS OF DISEASE, 7/E
38. Adenocarcinomas
- Peripheral lung locations.
- Associated with a history of smoking.
- It is the most common type of lung cancer occurring
never smokers.
- Histologically, the tissue may contain :
glands,
papillary structure,
bronchioloalveolar pattern,
cellular mucin, or
solid pattern if poorly differentiated.
: Abeloff's Clinical Oncology, 4th ed
39. - Solid and micropapillary patterns in
adenocarcinomas may predict a worse prognosis.
- Variants of adenocarcinomas include
-signet-ring,
-clear cell,
Primarily descriptive
-mucinous,
-fetal adenocarcinomas.
Distinct
Rare
Young smokers
Better Prognosis
: Abeloff's Clinical Oncology, 4th ed
41. Peripheral adenocarcinoma of the lung with pleural puckering.
:Fishman’s Pulmonary Diseases and Disorders 4th Edition
42. Bronchioloalveolar carcinoma (BAC)
subtype of adenocarcinoma
grows along the alveoli without invasion.
present radiographically as a single mass, as a
diffuse multinodular lesion, as a fluffy infiltrate.
on CT scans as a "ground-glass" opacity (GGO).
:Harrison's Principles of Internal Medicine, 18e
43. Bronchioloalveolar carcinoma, mucinous type. Tall columnar cells with abundant mucinous cytoplasm
line the alveolar septa
:Fishman’s Pulmonary Diseases and Disorders 4th Edition
44. Large cell carcinomas
-fewer than 10% of lung cancer.
- occur peripherally.
- poorly differentiated carcinomas
- sheets of large malignant cells, often with
associated necrosis.
- Cytologically, the tumor is also arranged in
syncytial groups and single cells.
:Harrison's Principles of Internal Medicine, 18e
45. Variants of large cell carcinoma:
- basaloid carcinoma- present as an endobronchial
lesion and may resemble a high-grade
neuroendocrine tumor,
- lymphoepithelioma-like carcinoma- similar to the
same-named tumor of other sites and is EpsteinBarr virus–related.
:Harrison's Principles of Internal Medicine, 18e
46. Large cell carcinoma, featuring pleomorphic, anaplastic
tumor cells and absence of squamous or glandular
differentiation.
:ROBBINS AND COTRAN PATHOLOGIC BASIS
OF DISEASE, 7/E
47. Immunohistochemistry
The diagnosis of lung cancer rests on the morphologic or cytologic features
correlated with clinical and radiographic findings.
Immunohistochemistry may be used :
1. To verify neuroendocrine differentiation within a tumor, with markers
such as neuron-specific enolase (NSE), CD56 or neural cell adhesion molecule
(NCAM), synaptophysin, chromogranin, and Leu7.
2. Helpful in differentiating primary from metastatic adenocarcinomas. For
example:Thyroid transcription factor 1 (TTF-1), is positive in more than 70% of
pulmonary adenocarcinomas and is a reliable indicator of primary lung
cancer, provided a thyroid primary has been excluded.
3. Cytokeratins 7 and 20 used in combination can help narrow the
differential diagnosis.
:Harrison's Principles of Internal Medicine, 18e
48. Common Immunohistochemical Markers Used in the
Diagnosis of Lung Tumors
:Harrison's Principles of Internal Medicine, 18e
Histology
Positive Immunohistochemical Markers
Squamous cell carcinoma
Cytokeratin (CK) cocktail, e.g., AE1/AE3
CK5/6 , CK7 rare
Adenocarcinoma
Cytokeratin cocktail, e.g., AE1/AE3
CK7 , TTF-1
Neuroendocrine markers rare, e.g., CD56,
NSE
Large cell carcinoma
Cytokeratin , TTF-1 rare
Neuroendocrine markers rare (e.g., CD56,
NSE)
Large cell neuroendocrine
carcinoma
Cytokeratin cocktail, e.g., AE1/AE3
TTF-1 , CD56 , Chromogranin
Synaptophysin
Small cell carcinoma
Cytokeratin cocktail (tends to be patchy)
TTF-1 , CD56 , Chromogranin
Synaptophysin
49. Molecular Pathogenesis
The exact cell of origin for lung cancers is not known.
In Lung adenocarcinoma , type II epithelial cells give
rise to tumors.
In SCLC, cells of neuroendocrine origin have been
implicated as precursors.
Lung cancer cells harbor multiple chromosomal
abnormalities ,including mutations, amplifications,
insertions, deletions, and translocations.
The earliest set of oncogenes found to be aberrant was
the MYC family of transcription factors (MYC, MYCN,
and MYCL).
:Harrison's Principles of Internal Medicine, 18e
50. Genes Somatically Altered in Different Histologic
Subtypes of Lung Cancer
Histology
Oncogene
Tumor-Suppressor
genes
Adenocarcinoma
EGFR
KRAS
ALK
TP53
CDKN2A/B(p16, p14)
LKB1
Squamous cell
carcinoma
EGFR
PIK3CA
IGF-1R
TP53
TP63
Small cell carcinoma
MYC
BCL-2
TP53
RB1
FHIT
Large cell carcinoma
(not well studied)
:Harrison's Principles of Internal Medicine, 18e
51. Early Detection and Screening
Low-dose, noncontrast, thin-slice helical or spiral
chest CT has emerged as a possible new tool for lung
cancer screening.
A major challenge confronting advocates of CT
screening is the high false-positive rate.
It appears that nodules:
<5 mm are unlikely to be cancerous and
5–10 mm in diameter are of uncertain significance.
:Harrison's Principles of Internal Medicine, 18e
52. Two additional screening studies are ongoing:
1.The National Lung Cancer Screening Trial (NLST), a
prospective comparison of spiral CT and standard chest
x-ray in 50,000 current or ex-smokers
2.Study in Europe comparing CT scanning with standard
of care in subjects with a history of heavy smoking.
:Harrison's Principles of Internal Medicine, 18e
53. Clinical Manifestations
Symptoms and Signs
Range of Frequency
Cough
8-75%
Weight loss
0-68%
Dyspnea
3-60%
Chest pain
20-49%
Hemoptysis
6-35%
Bone pain
6-25%
Clubbing
0-20%
Fever
0-20%
Weakness
0-10%
SVCO
0-4%
Dysphagia
0-2%
Wheezing and stridor
0-2%
:Harrison's Principles of Internal Medicine, 18e
54. Clinical findings suggestive of metastatic disease:
Symptoms elicited in history
Constitutional : weight loss > 10 lb
Musculoskeletal ; focal skeletal
pain
Neurologic: headache , syncope ,
seizures , extremity weakness
Signs found on physical examination
Lymphadenopathy(>1cm)
Hoarsness , superior vena cava
syndrome
Bone tenderness
Hepatomegaly (13> cm span)
Focal neurologic signs , papilledems
Soft – tissue mass
Routine laboratory tests
Hematocrit:<40% in men , <35% in
women
Elevated alkaline phosphatase , GGT
,SGOT and calcium levels
:Harrison's Principles of Internal Medicine, 18e
56. Paraneoplastic syndromes
SIADH – Small cell – Hyponatremia
Resolves within 1–4 weeks of initiating chemotherapy.
Demeclocycline can be a useful
ACTH-producing tumors – Small cell-Hypokalemia
No changes in body habitus. Metyrapone and ketoconazole
not effective.
Treatment is effective management of underlying SLCS
:Harrison's Principles of Internal Medicine, 18e
59. Neurologic–
Myopathic syndromes - 1%
Myasthenic Eaton-Lambert syndrome and retinal
blindness (SCLC).
Peripheral neuropathies,
Subacute cerebellar degeneration,
Cortical degeneration, and
Polymyositis
All lung cancer
types
60. Hematologic manifestations – 1-8%
-Migratory venous thrombophlebiti (Trousseau'ssyndrome),
-Nonbacterial Thrombotic (marantic) endocarditis with
arterial emboli,
-Disseminated intravascular coagulation
-Thrombotic disease complicating cancer is usually a poor
prognostic sign.
Renal manifestations – 1%
- Nephrotic syndrome and
- Glomerulonephritis
:Harrison's Principles of Internal Medicine, 18e
61. Eaton-Lambert syndrome.
-Autoimmune responses(anti–voltage-gated calcium channel
antibodies)
-Proximal muscle weakness, usually in lower extremities,
-Occasional - autonomic dysfunction
-Rarely - cranial nerve symptoms
-Frequently - depressed deep tendon reflexes
-In contrast to patients with myasthenia gravis, strength
improves with serial effort.
-Chemotherapy is the initial treatment of choice.
:Harrison's Principles of Internal Medicine, 18e
62. lung cancer-Metastasis
Adrenals - ~50% of cancers
Liver – 30-50%
Brain – 20%
Bone – 20%
:Harrison's Principles of Internal Medicine, 18e
63. The Solitary Pulmonary Nodule:A Systematic
Approach
A single discrete pulmonary opacity that is
surrounded by normal lung tissue.
Not associated with adenopathy or atelectasis.
Lesions larger than 3cm are almost always
malignant.
Solitary pulmonary nodules must be 3cmor less in
diameter.
Prompt diagnosis and resection are usually
advisable
:Fishman’s Pulmonary Diseases and Disorders 4th Edition
64. Factors influencing assessment of a solitary pulmonary nodule.
FACTOR
BENIGN
Pts
Malignant
Pts
1.Growth rate
No growth on 2 serial xrays at 3 mths interval
10
Definite growth on serial
X-rays
10
2.Calcification
a)Laminated
b)Dense
central core
c) Diffuse
Nodular
d) Punctate
central
10
10
Uncalcified
4
3.Age
<30yrs
9
>40yrs
4
4.Margin of lesion
Sharply defined
5
Ill defined
5
5.Size
Not a useful factor
0
Larger than 3.5cms
5
6.Density
Dense lesion <2cm
4
Low density <2cm
4
7.H/O malignancy
None
0
+ve
5
8.Documented
hemoptysis
None
0
+ve
5
10
10
IACM :Journal Vol.13 April-June 2012
65. Satisfies 1 of the Lesion rates 10 or
‘10 point’ items more on the ‘Malig
for benign ds.
nancy Scale’
Patient
considered to
have benign
nodule
Find out nature
of the lesion.
Thoracotomy is
indicated
Malignant
points minus
benign points
if <10
Fine needle
aspiration
biopsy
(without
resorting to
thoracotomy)
Plan specific
therapy
Accuracy of assessment was 77.7% in the series of the author(Jain DG ,1988)
IACM :Journal Vol.13 April-June 2012
67. Approach to solitory pulmonary nodule
New nodule identified on
standard CT scanning
Benign calcification pattern
on CT or stability for 2 yr on
archival films
yes
No further
testing
No
Risk factor
for surgery
No
Does probability of cancer
warrant further investigation ?
Harrison's Principles of Internal Medicine, 18e
68. :Harrison's Principles of Internal Medicine, 18e
Yes
Moderate
probability of
cancer(10-60%)
Low probability
of cancer
Serial highresolution CT
3, 6, 12, and 24 mo
No
-ve
test
Additional testing
-PET if nodule> 1 cm
in diamete
-Contrast- enhanced
CT, depending on
intitutional expertise
-Trans thoracic fineneedle aspiration
biopsy if nodule is
peripherallly located
-Bronchoscopy if air
bronchus sign present
+ve
test
Video-assisted
thoracoscopic surgery;
-examination of
mediastinal lymph
nodes and frozen
section folllowed by
lobectomy if nodule is
malignant