More than 99% of malignant lung tumors arise from the respiratory epithelium and are termed bronchogenic carcinoma. This type of carcinoma can be diveded in two main subgroups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).
While the incidence of almost all malignancies is falling or remaining stable, the incidence of lung cancer increases. Among women, it has surpassed those from breast carcinoma. Over the past 20-25 years, the male preponderance of 5-7:1 has fallen to 1.4:1 due to the increase in lung cancer among women. This changing pattern of disease is due to the post-World War II increase in cigarette smoking among the general population, and women in particular. Lung cancer is now the most common cause of cancer death for both sex.
Tabacco smoking - appears to be the most important risk factor. There is a dose-dependence relationship between both duration and intensity of smoking and mortality from lung cancer. Overall one in nine smokers develops lung cancer. Prospective and retrospective studies have demonstrated an increased death rate (8-20 times) from lung cancer in smokers versus nonsmokers. Heavy smokers (more than 25 cigarettes/day) experience a risk that is 20 times that of nonsmokers. There are over 2000 chemicals in cigarette smoke, several of them are either direct carcinogens or cocarcinogens. In humans smoking induces histologic changes in the bronchial epithelium including loss of bronchia cilia,, basal ephitelial hyperplasia and nuclear abnormalities.
Passive smoke - the exact risk of passive smoking remains controversial, current data suggest that there is a dose-response relation between extent of exposure and risk of cancer. A number of studies have shown increased risk for lung cancer in the spouses of smokers. Exposures to 25 smoker years in childhood approximately doubles the risk of lung cancer in a nonsmoker. Occupational - an increased risk is observed among workers in several industries as metallurgy, mining, manufacturing ofindustrial gases, pharmaceutical preparations, soaps and detergents, paints, inorganic pigments, and sinthetic rubber. Many environmental or occupational lung carcinogens have been identified, including arsenic, asbestos, chloromethyl methyl ether, bischloromethyl ether, chromium, ionizing radiation, mustard gas, nickel, polycyclic hydrocarbons, vinyl chloride, radon and certains manmade fibers.
Air pollution - studies demonstrate an increased incidence of lung cancer in urban versus rural environments (1.2:2.3), but the role of air pollution in carcinogenesis is uncertain. Individuals with heavy exposure to motor vehicle emissions do not appear to have an increased incidence of lung cancer.
General - COPD and chronic bronchitis attends with a great incidence in pulmonary carcinoma. Increased risk is also observed in individuals with a poor diet in b-carotene and vitamin A (vitamin A and its derivatives have potent effects on the differentiation of respiratory epithelium) but this conection has not been confirmed yet.
Nonmodifiable Risk Factors - there is a male predominance in lung cancer incidence and mortality in the United States. Black men have a high incidence of lung cancer too. Studies have demonstrated mendelian inheritance of a major autossomal gene governing susceptibility to lung cancer and it probably explain cancer in individuals with early age onset. Nowadays people discuss the role of P-450 enzyme in lung cancer (two isoenzymes have been implicated in susceptibility to lug cancer).
Type II cell in the alveolar epithelium is the stem cell that can proliferate. All subtypes of bronchogenic carcinoma are belived to be derived from the respiratory epithelium. The diferent histologic subtypes are the reflection of the diferent pathway taken by the tumor cells.
Successive accumulation of mutations in a number of genes involved in regulating growth and increased cellular proliferation is also necessary for carcinogenesis. The neuroendocrine cells of the lung contain many peptides wich are growth factors for bronchial epithelial cells (bombesine-like peptide and calcitonin gene-related peptide). Exposure to tabacco smoke causes a neuroendocrine cell hyperplasia in animals.
Others growth factors derived from inflamatory and epihtelial cells, may be elevated in tabacoo smokers and play a role in pathogenesis of lung cancer. Many chromosomal abnormalities may be present in carcinogenesis, including deletions ( involving chromosomes 3p, 5q, 9p, 11p, 13q and 17p ). The deleted region are often the loci of tumor supressor genes. Transformed oncogenes can be activated by mechanisms, including point mutation, gene amplification or overexpression (Ki-ras, H-ras, N-ras, myc family, her2/neu, c-kit, bcl-2).
Bronchogenic carcinoma produces a number of autocrine growth factors. Bombesin-like peptides are some of those. Tumor cells express receptors for them. Disrupting this autocrine growth factor loop, with monoclonal antibody or peptide antagonists can result in growth inhibition.
World Health Organization, divide lung cancewr into four major types: squamous or epidermoid, adenocarcinoma, large-cell carcinoma and small-cell carcinoma. Table-1 shows the histologic classification of malignant lung tumors.
Adenocarcinomas is now the most frequent histologic subtype. They are classically peripheral tumors arising from the peripheral airways and alveoli but may arise proximally from the epithelium or submucosal glands. The hallmark of adenocarcinomas is the tendency to form glands that may or may not produce mucin. Peripheral adenocarcinomas are sometimes associated with pulmonary scars. There may exist some dificulty in distinguing adenocarcinomas that have bronchial origin from many metastatic adenocarcinomas. When the adenocarcinoma has peripheral origin the dificulty increase and it may be dificult to distinguish either from metastasis or malignant mesothelioma.
Squamous cell carcinoma tends to originate in the central airways. This tipe of cancer arise from altered bronchial ephitelium and is preceded by years of progressive mucosal changes that include squamous metaplasia, dysplasia and carcinoma in situ. Microscopically, the are intercellular bridges and abundant keratin formation.
Large-cell carcinoma are usually loocated peripherally. These group of carcinomas are undifferentiated at the light microscope.They have large nuclei, prominent nucleoli, abundant cytoplasm and distinct cytoplasmic membranes. They may exhibit neuroendocrine or glandular differentiation markers when studied by immunohistochemistry or electronmicroscopy.
Smal-cell carcinomas usually develop proximally as large, bulk, soft, gray-white masses. SCLC is characterized by small, dark-staining cells with little cytoplasm. The diagnosis of SCLC is not usually difficult, but fine-needle aspirations of lymph nodes, applying immunohistochemical markers can be helpful.
In general 5-15% of patients are detected while asymptomatic, during a routin chest radiograph but the vast majority present with some sign or symptom. Cough, dyspnea, hemoptysis, stridor, wheeze and pneumonitis from obstruction are signs and symptoms from central or endobronchial growth. Pain from pleural or chest wall involvement, cough, dyspnea (restrictive) and symptoms of lung abscess resulting from tumor cavitation result from peripheral growth of the primary tumor. Tracheal obstruction, esophageal compression with disphagia, recurrent laringeal nerve paralysis with Horner's syndrome (miosis, ptosis, enophthalmus and ipsilateral loss of sweat) are consequence of local spread of tumor in the torax. Pancoast's syndrome ( shoulder pain that radiates in the ulnar distribution of the arm and often with radiologic destruction of the first and second ribs) result from growth of tumor in the apex with involvement of the eighth cervical and first and second thoracic nerves. Superior vena cava syndrome from vascular obstruction may be present. Pericardial and cardiac extension with resultant tamponade, arrhythmia or cardiac failure or pleural effusion as a result of lymphatic obstruction also may occur.
Autopsy studies have found lung cancer metastases in virtually every organ system. Metastatic disease is found at autopsy in over 50% of patients with epidermoid carcinoma, 80% of patients with adeno and large cell carcinoma and over 95% of patients with small cell cancer. Common clinical problems include brain metastasis with neurologic deficits; bone metastases with pain and patologic fractures; bone marow invasion with cytopenias or leukoerythroblastosis and myelophytisic anemia; liver metastases with biochemical dysfunction, biliary obstruction and pain;lymph node metastases; spinal cord compresion syndrome from epidural or bone metastases.
Paraneoplasic syndromes may be the presenting finding or sing of recurrence. They may be relived with the tretment of the tumor. We can find endocrine, neurologic, dermatologic, vascular, hematologic, conjunctive, imunologic and sistemic manifestations.
Imaging studies:
Chest radiograph is the most important radiologic study to diagnose lung cancer. It is important to obtain old radiographs when an abnormality is visualized. The growing time may be helpful to suggest a benign or malignant diagnosis. Doubling time < 6 weeks or > 18 months suggest a benign diagnosis. Presence of heavy calcification within a lesion is sing of benignity ( popcorn pattern ).
CT can help in detecting enlarged suspected lymph nodes (although biopsy is required) and detecting sites of metastases.
MRI studies are useful to detect vertebral, spinal cord and mediastinal structure invasion.
Pathologic diagnoses:
Sputum citopathologyWhen cell type is in doubt, obtaining additional tissue for pathologic study is required.
Staging is important to predict prognosis and determine the appropriate therapy.Tables 2, and 3 shows NSCLC staging and table 4 shows SCLC staging.
NSCLC therapy
Surgical - offers the best chance for curing. The incresed use of lung-sparing resections (sleeve lobectomy, segmentectomy, wedge resection and thoracoscopic wedge resection), has allowed surgical therapy for patients with less pulmonary reserve, but studies demonstrate that local recurrence rates are higher than non lung-sparing resections.
Radiation - controls local disease (10-20% of localized disease can be cured). Radiation therapy is most commonly used to palliate symptoms.
Chemotherapy - its effectiveness is controversial. Cisplatin, mitomycin, vinca alkaloids, infosfamide and etoposide are some used drugs. Benefits to this group are minimal.
Adjuvant therapy - in patients with resectable stage II or III NSCLC, there is a high risk for failure of surgical therapy due to local, mediastinal or distant metastatic recurrence. Radiation therapy decrease the risk of mediastinal recurrence but does not improve overall survival. Increased disease-free survival is achived in stage II and III resected NSCLC patients treated with chemotherapy or radiation therapy plus chemotherapy.
SCLC therapy
Chemoterapy is the cornerstone of treatement. Regiments containing etoposide and either carboplatin or cisplatin is belived to offer the best combination of efficacy and lack of toxicity. In patients with limited-stage disease concurrent or alternating chest radiation therapy with chemotherapy is used. In patients with extensive-stage SCLC, radiation is not used in the initial managemant because chemotherapy produces initial palliation in 80% or more cases. The radiation does not seem to increase survival.
Cecil - Textbook of Medicine 20th Edition
Harrison Internal Medicine 13th Edition
Pathologic Basis of Disease 5th Edition
Current Medical Diagnosis and Treatment 1997
The Washington Manual 28th Edition
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