Lung cancer

Jiang sheng-hua
 Malignant tumors are cancer. They can
invade and damage nearby healthy tissues
and organs. Cancer cells can also break
away from the tumor and enter the
bloodstream or the lymphatic system. That
is how cancer spreads and forms tumors in
other parts of the body. The spread of
cancer is called metastasis.
 Definition
 Bronchogenic carcinoma refers to the
malignant tumor which grows in the
bronchus. Originating from mucus or gland
of bronchus.
 Incidence and mortality
 Bronchogenic carcinoma has increased
remarkable in incidence and mortality
during half of the century and has become
the most frequent visceral malignant
diseases of men.The mortality of lung
cancer hold the first place among all kinds
carcinomas.
 Epidemiology
 Lung cancer is especially common among men in
North America, Europe, and Oceania. At the
moment, lung cancer rates are higher than ever
before among the people of central and Eastern
Europe. In Japan, lung cancer has increased
tenfold in men and eightfold in women since
1950.
 Chinese women, many of whom are nonsmokers,
have very high lung cancer rates. This
phenomenon has been associated with exposure to
cooking oil vapors and other forms of air pollution
in the indoor environments of China.
 Epidemiology
 Worldwide, lung cancer accounts for
approximately 13% of all cancer; more than
1.1 million cases of lung cancer are
diagnosed annually, and over 1 million
deaths are caused by the disease.
 The incidence and mortality of lung cancer
in American men and women reflect their
smoking habits
 Risk Factors
 Tobacco
 It is estimated that cigarette smoking is
responsible for approximately 85 to 90% of
all cases of lung cancer, including 90% of
cases in men and 80% in women. More than
40 carcinogens have been identified in
cigarette smoke
 The risk for development of lung cancer
correlates with:
 the number of cigarettes smoked per day
 lifetime duration of smoking,
 age at onset of smoking,
 tar and nicotine content of the cigarettes
 degree of inhalation,
 use of unfiltered cigarettes
 Environmental Tobacco Smoke
 Exposure to environmental tobacco smoke
(i.e., passive smoking) by nonsmokers,
increases the risk for development of lung
cancer.

 Theexposure levels of environmental

tobacco smoke depend on the size of the
enclosed space and the intensity of smoking
 Other Exposure
 carcinogens for lung cancer: radon,
asbestos, arsenic, beryllium,
bis(chloromethyl)ether, cadmium,
chromium, nickel, vinyl chloride, and
polycyclic aromatic hydrocarbons (PAHs)
 Preexisting Lung Disease
 Tobacco smoking causes chronic
inflammation and destruction of lung tissue,
which results in chronic obstructive
pulmonary disease (COPD).
 patients in whom idiopathic pulmonary
fibrosis or pulmonary fibrosis from
asbestosis or silica develops are at increased
risk for the development of lung cancer
 Dietary Factors
 Increased consumption of fruits and green and
yellow vegetables is associated with a reduced risk
for lung cancer,
 low serum concentrations of antioxidant vitamins
such as vitamins A and E are associated with the
development of lung cancer.
 β-carotene supplementation increases the
incidence of lung cancer
 Gender and Racial Differences
 Women who smoke have a 1.2- to 1.7-fold
higher risk ratio than men do, especially for
adenocarcinoma and SCLC.
 (1) effects of hormones such as estrogen on
the development of lung cancer,
 (2) gender differences in nicotine
metabolism,
 (3) gender variations in cytochrome P-450
enzymes involved in the bioactivation of
toxic components in cigarette smoke
condensate
 Human Immunodeficiency Virus
Infection
 Some studies suggest that the risk for lung
cancer is increased in patients infected with
human immunodeficiency virus (HIV)
mostly as a result of cigarette smoking.
Most patients are male (10:1) and young, in
part reflecting the demographics of HIV
infection
 Inheritance
 First-degree relatives of patients with lung cancer
have a two- to six-fold increase in the risk for lung
cancer after adjusting for tobacco use.
 Second-degree relatives of lung cancer patients
have a relative risk of 1.28,
 third-degree relatives have a relative risk of 1.14.
Nonsmokers with a family history of lung cancer
have a two- to four-fold increased risk for lung
cancer.
 Pathobiology
 the loss of normal control mechanisms of cellular
growth
 (1) oncogenes result in activation and gain of
function;
 (2) tumor suppressor genes, which are “cancer”
genes in which loss of function by mutation
removes inhibitions to control cell growth,
 (3) growth factors
 Oncogenes
 ras, the myc family, HER-2/neu (c-erB),
and Bcl-2.
 The ras family of oncogenes has three
primary members (H-ras, K-ras, and N-
ras),
 Amplification and overexpression of the
myc family oncogenes (a-myc, L-myc, N-
myc) are seen in 10 to 40% of SCLC and
10% of NSCLC.
 The HER-2/neu (c-erB-2) gene, which encodes
growth factor receptor or p185 neu (a tyrosine
kinase glycoprotein), is activated in NSCLC but
not SCLC.
 Overexpression of HER-2/neu in patients with
adenocarcinoma of the lung portends a poor
survival. Bcl-2, an oncogene that encodes a
protein that inhibits programmed cell death
(apoptosis), is also overexpressed in lung cancer,
especially in SCLC.
 Tumor Suppressor Genes
 The p53 tumor suppressor gene encodes for
a nuclear phosphoprotein that controls cell
division in normal as well as malignant
cells.
 If normal cell DNA is damaged, p53 causes
cellular arrest in either the G1/S phase or
the G2/mitosis phase or induces apoptotic
death.
 retinoblastoma (Rb) gene
 The retinoblastoma (Rb) gene, located at the
chromosome 13q14 region, encodes a nuclear
phosphoprotein that regulates G1/S phase cell
cycle checkpoints by binding to cyclin D and
various transcription factors
 When Rb does not function, the G1/S phase
checkpoint is uncontrolled, thereby leading to cell
proliferation and malignant transformation.
 the deletion of genetic material on the short
arm of chromosome 3(3p)(p14-p23).
 The deletion occurs in approximately 50%
of NSCLC and 90% of SCLC. The FHIT
(fragile histidine triad) gene (3p14.2) is
abnormal in many lung cancers and may
function as a tumor suppressor gene by
suppressing tumor growth and causing
apoptosis.
 Growth Factors
 Growth factors secreted by lung cancer cells
may reflect adjacent or regional cells
(paracrine stimulation) or cause
autonomous proliferation of the cells from
which they were secreted (autocrine
stimulation). Cells that are affected by this
autocrine stimulation secrete a biologically
active growth factor. Antibodies that bind to
this growth factor will inhibit cell growth.
 Autocrine (peptide) growth factors that are
important in the growth of lung cancer cells,
particularly SCLC, include gastrin-releasing
peptide (GRP), insulin-like growth factor
type I (IGF-I), and hepatocyte growth
factor. GRP occurs in approximately 20 to
60% of SCLC and less frequently in
NSCLC. Hepatocyte growth factor is
expressed mainly in NSCLC.
 Epigenetics
 Epigenetics refers to a change in gene
expression that is heritable but does not
involve a change in DNA sequence
 changes in DNA methylation. include
hypomethylation, dysregulation of DNA
methyltransferase I, and hypermethylation.
 Clinical Manifestations
 (1) caused by the pulmonary lesion itself—
local tumor growth, invasion, or
obstruction;
 (2) intrathoracic—regional tumor spreading
to lymph nodes and adjacent structures;
 (3) extrathoracic—distant spread of disease;
 (4) paraneoplastic syndromes.
 Pulmonary Lesion
 Symptoms resulting from the primary lung
cancer depend on the location and size of
the cancer. Such symptoms can be
secondary to endobronchial or peripheral
growth of the primary tumor.
 cough occurs in approximately 45% of
cases, but it is nonspecific and also common
in patients who smoke and have COPD
 Hemoptysis occurs in more than 30% of
patients, but the most common causes of
hemoptysis are bronchitis and
bronchiectasis
 Dyspnea also occurs in 30 to 50% of
patients.
 Wheezing is uncommon as an initial
symptom in lung cancer and may signify
major airway obstruction.
 Lesions may be cavitary and may be
associated with an abscess at the time of
diagnosis of the lung cancer.
 Peripheral lung tumors may be
asymptomatic but are more frequently
associated with symptoms of cough and pain
from involvement of the pleura or chest
wall.
 Chest pain which occurs in more than 25%
of patients, may be dull in nature, but chest
pain that is severe and persists may be due
to chest wall involvement
 Intrathoracic Spread
 Dysphagia may occur secondary to esophageal
compression. coughing associated with swallowing or
the development of aspiration pneumonitis should point
to this possibility.
 Hoarseness which is associated with recurrent laryngeal
nerve paralysis, occurs in less than 20% of cases; it is
more common with left-sided lung tumors because the
nerve on this side has a longer intrathoracic course than
the right-sided nerve does.
 Phrenic nerve paralysis with hemidiaphragmatic elevation
is associated with dyspnea and hiccups. Apical tumors,
such as superior sulcus NSCLC (Pancoast's syndrome),
may cause Horner's syndrome pain secondary to rib
destruction, atrophy of hand muscles, and pain in the
distribution of the C8, T1, and T2 nerve roots because of
tumor invasion of the brachial plexus.
 Blockage of the superior vena cava (SVC) as a
result of compression or direct invasion by the
tumor itself or by enlarged mediastinal lymph
nodes may cause dyspnea.
 Other manifestations of intrathoracic spread
include pleural effusion causing dyspnea;
pericardial effusion and cardiac extension of
the tumor causing heart failure, arrhythmia, or
tamponade; and lymphangitic spread through
the lungs causing dyspnea and hypoxemia.
 Extrathoracic Spread
 Bone metastasis occurs in 30 to 40% of patients
with lung cancer and commonly involves the
vertebrae, ribs, and pelvic bones. Pain is the
primary symptom.
 Liver metastases can produce right upper
quadrant abdominal pain, as well as nonspecific
symptoms of fatigue and weight loss.
 Adrenal metastases can cause pain but most often
cause no symptoms. One gland is usually
involved, but bilateral metastases may occur.
 Brainmetastasis may cause no symptoms but is
more commonly associated with nausea, vomiting,
headaches, seizures, confusion, personality
changes, and focal neurologic signs and
symptoms, depending on the site of metastatic
disease.
 Epidural, intramedullary spinal cord metastasis
and diffuse leptomeningeal involvement are less
common than cerebral and cerebellar metastases.
 Paraneoplastic Syndromes
 Endocrine syndromes include hypercalcemia the
syndrome of inappropriate antidiuretic hormone
secretion and ectopic adrenocorticotropic hormone
secretion ,Other endocrine paraneoplastic
syndromes of lesser clinical significance produce
hormones such as the β-subunit of human
chorionic gonadotropin, prolactin, gastrin, growth
hormone, thyroid-stimulating factor, insulin-like
substance, and calcitonin.
 Neurologic syndromes are relatively rare, are most
commonly associated with SCLC and may have
autoimmune mechanisms. Such syndromes
include Eaton-Lambert syndrome ,limbic
encephalopathy, cerebellar degeneration, subacute
sensory neuropathy, autonomic neuropathy . and
optic neuritis .Skeletal manifestations include
digital clubbing and hypertrophic pulmonary
osteoarthopathy
 Hematologic/vascular syndromes include
hypercoagulable states , migratory
thrombophlebitis (Trosseau's syndrome),
and nonbacterial thrombotic endocarditis ,
Cutaneous manifestations include
dermatomyositis , acanthosis nigricans,
erythema gyratum repens, and
hyperkeratosis of the palms and soles of the
feet.
 Diagnosis
 cytologic examination of tissue biopsy specimens,
sputum , bronchial washings and brushings of
suspicious lesions , bronchoalveolar lavage fluid,
and transbronchial and transthoracic needle
aspirates ,
 The greater number of viable tumor cells in biopsy
specimens from transthoracic, endobronchial,
transbronchial, or open biopsy procedures increases
the probability of accurate diagnosis
 Radiographic Findings
 The appearance on the x-ray film depends
on the position ,size and stage of the tumor
1.Peripheral type :It may be various such as
infiltrative or nodular, lobulated or
umbilicus sign,liner protrusions from the
shadow into the surrounding lung, cavitation
which is often eccentric irregular in the
inner wall owing to the necrosis of the
neoplasm.
 Radiographic Findings
2 Central type
 (1) Direct appearance :Unilateral
enlargement of the hilar shadow due to the
tumor itself or enlarged lymph nodes.
 (2) Indirect appearance :Including local
emphysema;obstructive pneumonia either
lobal or segmental; obstractive atalectasis
(collapse) lobe or segment.
 Advantage of CT:
 (1) Some small lesion, lesion behind of
cardiac or blood vessel,and pathology
located in apical of lung can be found by
CT which can’t be found by chest x-ray.
 (2) Lymph nodes along hilar or mediastina
can be found by CT.
Fig1 Atelectasis,Right upper
lobe
Fig3 Mass With Fuzzy,Right
Fig4 Mass In right
Lobe,Lateral
portion
Fig5 Cavitating Bronchial
 Examination of sputum
 Cytologic examination of bronchial
secretions(or sputum)may reveal exfoliated
malignant cells recognizable to the
pathologist who is specially trained for such
work.The sputum must to be fresh, send on
time, repeat(4-6 times)..
 Bronchoscope
 Bronchoscope may verify the existence of
tumor , of Central type, and cytologic
diagnosis of lung cancer should be obtained
though FBC
 .Blind biopsy may be help to the diagnosis
of the tumor beyond the range of
bronchoscope vision
Fig 1 Normal Trachea Fig 2 Normal Carina
Fig 3 Squamous Cell Fig 4 Adenocarcinoma
Carcinoma, Trachea Left Lingular Bronchus
Fig 5 Adenocarcinoma Fig 6 Extrinsic Pressure
Right Truncal Intermedus Trachea
 Pathology And Classification
 1. According to the position of tumor arising
from ,it can be divided into two types .
 Central type:Tumor arises from main
bronchus, lobar and segmental bronchus .
Peripheral type : Tumor arises beyond
segmental bronchus .
Pathology And Classification

According to the different principles

of management,it is divided into two
types.
SCLC:small cell lung carcinoma.
NSCLC:non small cell lung carcinoma.
Pathology And Classification
 2.According to cytology,it is convenient to
classify into four kinds of types.
 (1).Squamous cell carcinoma.
 (2).Small cell anaplastic carcinoma.
 (3).Large cell anaplastic carcinoma.
 (4).Adenocarcinoma(including alveolar
cell carcinoma).
 NSCLC accounts for approximately 85% of all
lung cancer. NSCLC subtypes include
adenocarcinoma (40%), squamous cell carcinoma
(30%), and large cell carcinoma (15%). SCLC
accounts for 15% of all lung cancer. Other less
common pulmonary neoplasms include
adenosquamous carcinoma, carcinoid tumors,
bronchial gland tumors, soft tissue tumors (e.g.,
sarcomas), pulmonary blastomas, and lymphoma.
 Staging
T = tumor size
 N = node involvement
 M = metastasis status
 Staging
 Staging of NSCLC involves classification
according to T (tumor size), N (regional lymph
node involvement), and M (presence or absence of
distant metastases)
 For SCLC, TNM staging is not generally used;
rather, SCLC is staged as limited disease, defined
as disease that can be encompassed by a single
radiation portal, or extensive disease, that
extending beyond a single radiation portal (usually
metastatic
 SCLC Stage
 Limited

Primary tumor contained to hemithorax.

Ipsilateral hilar lymph nodes.
Ipsilateral and contralateral supraclavicular lymph
nodes.
Ipsilateral and contralateral mediastinal lymph
nodes.
 Extensive
Metastatic lesions in the contralateral lung.
Distant metastatic involvement (for
example, brain, bone, liver, or adrenal
glands).
Pleural effusion
 Staging Procedures
 For patients with SCLC, the initial
pretreatment staging evaluation is similar to
that used for NSCLC patients. For patients
with peripheral blood count abnormalities,
bone marrow aspiration and biopsy are
recommended. Twenty to 30% of patients
with SCLC will have tumor in bone marrow
at the time of diagnosis.
 Radiography
A standard posteroanterior and lateral chest
radiograph, though inexpensive and easy to
perform, has limited value in the staging of
lung cancer. Although it can detect
pulmonary nodules as small as 3 to 4 mm, it
is not reliable in detecting hilar or
mediastinal lymphadenopathy
中央型肺癌
周围型肺癌
 Computed Tomography
A CT scan is commonly used to evaluate
whether lung cancer is present in the hilar
and mediastinal lymph nodes, liver, and
adrenal glands, but its accuracy in
identifying mediastinal lymph node
involvement is suboptimal
 Positron Emission Tomography
 PET, which uses 2-[18F]fluoro-2-deoxy-D-
glucose to identify areas of increased
glucose metabolism in lung tumors, is more
sensitive than CT in staging lung cancer
Evaluation of Mediastinal Tissue
 Afterinitial clinical staging, if a patient
with NSCLC has potentially surgically
resectable disease, the regional lymph nodes
(mediastinum) must be sampled for possible
metastases. Fiberoptic bronchoscopy to
assess the bronchi and transbronchial needle
aspirates to evaluate for mediastinal
lymphadenopathy are recommended.
Transbronchial needle aspirates are
positive in 35 to 40% of patients when
a CT scan demonstrates hilar or
mediastinal lymphadenopathy. The
larger the size of the lymph node on
CT scan, the greater the chance for the
aspirate to be positive
 Treatment
 Non–Small Cell Lung Cancer

 Small Cell Lung Cancer

 Stage I and II Disease
 surgery is the initial treatment of choice
 pulmonary function tests (forced expiratory
volume at 1 second [FEV1] and diffusing
capacity of the lung for carbon monoxide
[Dlco]), as well as blood gas analysis
A preoperative FEV1 less than 40% of
predicted and a Dlco less than 40% of
normal are associated with an increase in
operative mortality.
 Other factors for determining resectability
include exercise tolerance and comorbid
disease.
 chemotherapy
 Adjuvant cisplatin-based chemotherapy (e.g.,
cisplatin, 80 mg/m2 every 3 weeks for four doses
or 100 mg/m2 every 4 weeks for three or four
doses, or cisplatin, 120 mg/m2 every 4 weeks for
three doses, plus etoposide, 100 mg/m2 for 3
days/cycle, vinorelbine, 30 mg/m2 weekly,
vinblastine, 4 mg/m2 weekly, or vindesine, 3
mg/m2 weekly) provides a small absolute increase
in overall survival at 5 years for stage I, II, and III
disease. Treatment with monoclonal antibodies
has not yet been consistently beneficial
 Adjuvant radiation therapy
 Adjuvant radiation therapy for stage I and II
disease is not indicated. However, in
patients with stage I NSCLC who for
medical reasons are not candidates for
surgery, radiation therapy (usually a total
dose of 65 to 70 Gy in 2-Gy fractions) can
be given with curative intent. Five-year
survival rates in patients thus treated range
from 10 to 30%.
 Stage III—Resectable
 surgeryalone is suboptimal treatment
because of the presence of occult metastatic
disease. Neoadjuvant (i.e., induction)
chemotherapy given in sequence with or
concurrent with radiation therapy before
surgery improves survival when compared
with surgery alone or surgery plus
postoperative radiation therapy.
 Stage III—Unresectable
 Stage IIIA or IIIB disease may be unresectable.
Thoracic radiation therapy (total dose, 60 Gy)
relieves symptoms in the chest but has little effect
on 5-year survival rates unless combined with
induction chemotherapy (e.g., vinblastine plus
cisplatin for two cycles), which improves median
survival from 9.7 months to 13.8 months and the
5-year survival rate from 7 to 19% when
compared with radiation therapy alone
 Concurrent chemotherapy and radiation therapy
rather than sequential therapy can improve
survival in patients with locally advanced NSCLC
but increases side effects, particularly esophagitis,
by five-fold.
 To improve the effectiveness of radiation therapy,
different fractionation approaches are under
evaluation. Three-dimensional treatment planning
permits delivery of higher doses of radiation to the
primary tumor and regional lymph nodes without
increasing toxicity
Stage IV—Disseminated Disease
 treatment generally consists of cisplatin or
carboplatin combined with paclitaxel, docetaxel,
gemcitabine, vinorelbine, irinotecan, or topotecan.
 Data suggest that two-drug combinations are
better than single-agent therapy, but three-drug
combinations are not more effective than two-drug
combinations. The duration of therapy is four to
six cycles
 Small Cell Lung Cancer
 Themainstay of treatment of SCLC is
chemotherapy because the disease is
characterized by its propensity for a rapid
growth rate and spread to distant sites.
Unfortunately, management of SCLC has
changed little in the past decade
 Limited Stage
 Management usually consists of
chemotherapy and radiation therapy, and
surgery is indicated only in the
approximately 5% of patients who have a
solitary peripheral pulmonary nodule
without evidence of mediastinal lymph
node involvement with clinical staging
 Ifthe nodes contain metastases, chest irradiation is
recommended in addition to chemotherapy.
 the high rate of brain metastases with SCLC,
reduces the risk for brain metastases and provides
about a 5% survival advantage, but its higher risk
of precipitating cognitive abnormalities must be
taken into consideration, especially in elderly
patients.
 肺癌脑转
移
 Extensive Stage
 For extensive-stage SCLC, chemotherapy is the
treatment of choice. In the United States,
etoposide plus cisplatin or carboplatin is
commonly used. The latter regimen causes
significantly less nausea, vomiting, and
neurotoxicity because of the carboplatin. The
chemotherapy is administered every 3 weeks for
four to six cycles. At this time there is no evidence
that maintenance therapy with either
chemotherapy or targeted molecular therapy
increases survival rates
 Screening
 Spiral CT scanning is four- to five-fold
more sensitive than chest radiography for
detecting malignant nodules in high-risk
patients, but spiral CT also detects seven to
eight benign nodules for every malignant
nodule found. A large trial is currently
ongoing to determine whether current or
former smokers benefit from screening with
spiral CT.
【预防 】

【预后 】
 Prevention
 prevent individuals from smoking and promotion
of smoking cessation
 Trials of supplemental doses of β-carotene and
vitamin E,
 High concentrations of selenium in blood are
associated with a lower risk for lung cancer, and
an ongoing trial is comparing selenium with
placebo in patients who have survived resection
for stage I lung cancer.
 Prognosis
 Mostpatients in whom lung cancer is
diagnosed have incurable disease, with an
overall 5-year survival rate of
approximately 15%. What determines the
chance for survival is the stage of disease in
NSCLC and whether the disease is
extensive or limited in the case of SCLC
谢谢