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. exposure levels of environmental tobacco smoke depend on the size of the enclosed space and the intensity of smoking

 The

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 Nras),  Amplification and overexpression of the myc family oncogenes (a-myc, L-myc, Nmyc) 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

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.

also occurs in 30 to 50% of

 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. 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.

 Hoarseness

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.

 Brain

metastasis 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 biopsy may be help to the diagnosis of the tumor beyond the range of bronchoscope vision

 .Blind

Fig 1 Normal Trachea

Fig 2 Normal Carina

Fig 3 Squamous Cell Carcinoma, Trachea

Fig 4 Adenocarcinoma Left Lingular Bronchus

Fig 5 Adenocarcinoma Right Truncal Intermedus

Fig 6 Extrinsic Pressure Trachea

Pathology And Classification
 1.

According to the position of tumor arising type:Tumor arises from main

from ,it can be divided into two types .
 Central

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 NSCLC:non

cell lung carcinoma. 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-Dglucose to identify areas of increased glucose metabolism in lung tumors, is more sensitive than CT in staging lung cancer

Evaluation of Mediastinal Tissue
 After

initial 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
 surgery

alone 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
 The

mainstay 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

 If

the 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
 Most

patients 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