Ppt lung carcinoma part1

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.

 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

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

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.


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

Lung cancer incidence in United States between 1975 and 2003. Age-adjusted to the
2000 U.S. standard population


Tobacco use and lung cancer mortality in the United States 1900–2002.
*Per 100,000, age-adjusted to the 2000 U.S. standard population

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

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.

 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

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

 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


 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.


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.

 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


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.


 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.




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.


Pathology

 The term lung cancer is used for tumors

arising from the respiratory epithelium
(bronchi, bronchioles, and alveoli).


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

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

 Adenosquamous carcinoma
 Sarcomatoid carcinoma
Pleomorphic carcinoma
Spindle cell carcinoma

Giant cell carcinoma
Carcinosarcoma
Pulmonary blastoma
 Carcinoid tumor
Typical carcinoid tumor
Atypical carcinoid tumor
 Salivary gland tumors
Mucoepidermoid carcinoma
:Fishman’s Pulmonary
Diseases and Disorders
4th Edition

Adenoid cystic carcinoma
Epithelial-myoepithelial carcinoma

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

Epithelial cell lung cancers
WESTERN COUNTRIES

Squamous
Large

INDIA-1986-2001

Others
Adeno

Small


Squamous

Large
Adeno


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.


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

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

 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


 Differential diagnosis :

-poorly differentiated nonsmall cell carcinomas
-neuroendocrine carcinomas,
poorly differentiated squamous cell carcinoma
-nonepithelial tumors
lymphoma,
small round blue cell tumors,
sarcomas (e.g., synovial sarcoma).

Small cell carcinoma with islands of small deeply
basophilic cells and areas of necrosis
:ROBBINS AND COTRAN PATHOLOGIC BASIS OF
DISEASE, 7/E

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

 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.


 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.


Well-differentiated squamous cell carcinoma showing
keratinization

DISEASE, 7/E

Cavitation within a squamous cell carcinoma.

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

 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.


- 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

Gland-forming adenocarcinoma

DISEASE, 7/E

Peripheral adenocarcinoma of the lung with pleural puckering.


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).


Bronchioloalveolar carcinoma, mucinous type. Tall columnar cells with abundant mucinous cytoplasm
line the alveolar septa


 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.


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.


Large cell carcinoma, featuring pleomorphic, anaplastic
tumor cells and absence of squamous or glandular
differentiation.

:ROBBINS AND COTRAN PATHOLOGIC BASIS
OF DISEASE, 7/E

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.


 Common Immunohistochemical Markers Used in the

Diagnosis of Lung Tumors

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


Cytokeratin cocktail (tends to be patchy)
TTF-1 , CD56 , Chromogranin
Synaptophysin

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).


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


MYC
BCL-2

TP53
RB1
FHIT

Large cell carcinoma
(not well studied)


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.

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.


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%

 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


Syndromes/Symptoms secondary to regional
metastases:
 Esophageal compression  dysphagia
 Laryngeal nerve paralysis  hoarseness
 Symptomatic nerve paralysis  Horner’s syndrome





(enophthalmos, ptosis, miosis, and anhidrosis)
Cervical/thoracic nerve invasion  Pancoast syndrome.
Lymphatic obstruction  pleural effusion
Vascular obstruction  SVC syndrome
Pericardial/cardiac extension  effusion, tamponade


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

 PTH/PTH-rp – Squamous cell – Hypercalcemia
Clinical symptoms include nausea, vomiting,
abdominal pain, constipation, polyuria, thirst,
and altered mental status.
 Calcitonin
 Gonadotropin
 Serotonin

Skeletal–
 Clubbing - 30% (usually NSCLCs)

 Hypertrophic primary osteoarthropathy - 1–10%
(usually adenocarcinomas).
 Periostitis

Cutaneous manifestations – 1%
- Dermatomyositis and
- Acanthosis nigricans


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

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


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.


lung cancer-Metastasis
 Adrenals - ~50% of cancers
 Liver – 30-50%
 Brain – 20%
 Bone – 20%


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


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

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

Differential Diagnosis of Solitary
Pulmonary Nodules:
Malignant tumors

Infectious granulomas

Bronchogenic carcinoma
(adenocarcinoma, large cell,
squamous, small cell)
Carcinoid
Pulmonary lymphoma

Tuberculosis
Histoplasmosis
Coccidioidomycosis

Benign tumors

Others

Hamartoma
Adenoma
Lipoma

Miscellaneous
BOOP
Abscess

Noninfectious granulomas

Pseudotumor
Spherical pneumonia
Pulmonary infarction
Arteriovenous malformation
Bronchogenic cyst
Amyloidoma

Rheumatoid arthritis
Wegener’s granulomatosis
Sarcoidosis
Paraffinoma

:Fishman’s Pulmonary Diseases and Disorders
4th Edition

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 ?



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

Ppt lung carcinoma part1

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