eMedicine Specialties > Oncology > Carcinomas of the Lung and Other Intrathoracic Carcinomas

Lung Cancer, Non-Small Cell

Author: Syed Huq, MD, Fellow, Division of Hematology-Oncology, Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Ellis Fischel Cancer Center
Coauthor(s): Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia; Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Contributor Information and Disclosures

Updated: Feb 18, 2010

Introduction

Background

Lung cancer is the leading cause of cancer-related mortality in both men and women in the United States and throughout the world. The prevalence of lung cancer is second only to that of prostate cancer in men and breast cancer in women. Lung cancer recently surpassed heart disease as the leading cause of smoking-related mortality. Most lung carcinomas are diagnosed at an advanced stage, conferring a poor prognosis.

The need to diagnose lung cancer at an early and potentially curable stage is obvious. In addition, most patients who develop lung cancer have been smokers and have smoking-related damage to the heart and lungs, making aggressive surgical or multimodality therapies less viable options.

Pathophysiology

Lung cancers are generally divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Non–small cell lung cancer accounts for approximately 85% of all lung cancers. Non-small cell lung cancer is divided further into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma histologies. All share similar treatment approaches and prognoses but have distinct histologic and clinical characteristics.

Recently, advanced molecular techniques have identified amplification of oncogenes and inactivation of tumor suppressor genes in non-small cell lung cancer. The most important abnormalities detected are mutations involving the ras family of oncogenes. The ras oncogene family has 3 members: H-ras, K-ras, and N-ras. These genes encode a protein on the inner surface of the cell membrane with GTPase activity and may be involved in signal transduction.

Studies performed on mice suggest the involvement of ras mutations in the molecular pathogenesis of non-small cell lung cancer. Studies in humans suggest that ras activation contributes to tumor progression in persons with lung cancer. The ras gene mutations occur almost exclusively in adenocarcinoma and are found in 30% of such cases. These mutations were not identified in adenocarcinomas that developed in persons who do not smoke. The K-ras mutation appears to be an independent prognostic factor. Studies are ongoing to develop management plans according to the presence or absence of ras gene mutations.

Other molecular abnormalities found in non-small cell lung cancer include mutations in c-myc and c-raf among oncogenes and retinoblastoma (Rb) and p53 among tumor suppressor genes.

Although tobacco smoking is the major cause of lung cancer, it now believed that there may be differences in susceptibility to carcinogenic effects of tobacco smoke among males and females. This may be due to differences in DNA repair mechanisms. Although still considered controversial, it is well known that women are more likely to develop adenocarcinomas, and stage for stage women live longer than men. In addition, differences in response to certain biologic therapies (ie, epidermal growth factor inhibitors) and anti-angiogenic agents have been observed between sexes.

A minority of lung cancers develop in those who have never smoked. These lung cancers are genetically distinct from smoking-related non-small cell lung cancer and may have therapeutic implications. The observed genetic differences include a lower frequency of K-ras and a higher frequency of mutations in epidermal growth factor receptor and likely are responsible for the higher efficacy of epidermal growth factor receptor inhibitors in this patient population.

Frequency

United States

The American Cancer Society projected that 215,020 cancers of the lung and bronchus would be diagnosed in the United States in 2008, with 114,690 cases in males and 100,330 cases in females.1

International

Lung cancer remains the most common malignancy in the world. In 2007, an estimated 1.5 million new cases of lung cancer were diagnosed globally, accounting for approximately 12% of the global cancer burden. An estimated 1.35 million lung cancer deaths occurred in 2007. Several differences exist in lung cancer incidence according to geographic area. Among males, the highest incidence of lung cancer occurs in Eastern Europe, North America, and Russia, while incidence is lowest in Africa and South Asia. Despite a very low incidence of smoking, Chinese females have a higher incidence of lung cancer than European females.

Global lung cancer trends have followed the trends in smoking with a lag time of several decades. Lung cancer incidence has been declining in several countries, including the United States, Canada, the United Kingdom, and Australia, following the decreasing incidence of smoking. Lung cancer incidence among women, however, continues to increase in several parts of the globe, although it has begun to plateau in the United States.

Mortality/Morbidity

  • Worldwide, an estimated 1,351,000 deaths due to lung cancer occurred in 2007 (975,000 in men and 376,000 in females).
  • Lung cancer is highly lethal, with the highest recorded 5-year patient survival rates (14%) observed in the United States. In Europe, the 5-year overall survival rate is 8%, similar to that of the developing world.
  • The American Cancer Society projected that deaths related to lung cancer would total 161,840 (90,910 in males and 71,030 in females) in the United States in 2008, accounting for 29% of all cancer-related deaths.1
  • Women diagnosed with non-small cell lung cancer (NSCLC) who take estrogen-progestin were found to have an increased mortality compared with women who have NSCLC and do not take hormone therapy. Secondary analyses of the Women's Health Initiative (WHI) randomized, placebo-controlled trial were performed on those taking daily conjugated equine estrogen (CEE, 0.625 mg) plus medroxyprogesterone acetate (MPA, 2.5 mg).2 The analyses included 16,608 multiethnic postmenopausal women aged 50-79 years and assessed the association of hormone therapy on lung cancer incidence and mortality. Confirmation of lung cancers was completed by medical record review. Results showed that the use of CEE plus MPA for more than 5 years increased a woman's risk for non-small cell lung cancer mortality, the leading cause of cancer death in women. This area deserves more attention and study to determine the risks and benefits of hormone therapy for postmenopausal women who smoke.

Race

Trends in 5-year survival rates in lung cancer from 1975-2003 revealed that while modest gains occurred in 5-year survival rates among whites, survival rates remained unchanged in the African American population. Current 5-years survival rates are estimated to be 16% among whites and 13% among non-whites.

Sex

  • Lung cancer is more common in men than in women. In the United States, Northern Europe, and Western Europe, the prevalence of lung cancer has been decreasing in men. In Eastern and Southern European countries, the incidence of lung cancer has been rapidly increasing. Most Western countries have encountered a disturbing trend of increasing prevalence in women and younger patients.
  • In the United States, the probability of developing lung cancer remains equal in both sexes until age of 39 years (0.03% or approximately 1 in 3,000). It then starts to increase among men compared to women to reach a maximum in those older than 70 years (6.74% vs 4.61% or 1 in 15 vs 1 in 22, among men and women respectively).

Age

The probability of developing lung cancer remains very low until age 39 years in both sexes. It then slowly starts to rise and peaks among those older than 70 years. The risk of developing lung cancer remains higher among men in all age groups after age 40 years.

Clinical

History

Lung cancers manifest with symptoms produced by the primary tumor, locoregional spread, metastatic disease, or ectopic hormone production. See the image below for a summary of all signs and symptoms. Approximately 7-10% of patients with lung cancer are asymptomatic and their cancers are diagnosed incidentally after a chest radiograph (CXR) performed for other reasons. The symptoms produced by the primary tumor depend on its location (ie, central, peripheral).

Non–small cell lung cancer. Symptoms and si...

Non–small cell lung cancer. Symptoms and signs of lung cancer.

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Non–small cell lung cancer. Symptoms and si...

Non–small cell lung cancer. Symptoms and signs of lung cancer.

  • Symptoms due to primary tumor
    • Central tumors are generally squamous cell carcinomas and produce symptoms of cough, dyspnea, atelectasis, postobstructive pneumonia, wheezing, and hemoptysis.
    • Most peripheral tumors are adenocarcinomas or large cell carcinomas and, in addition to causing cough and dyspnea, can cause symptoms due to pleural effusion and severe pain as a result of infiltration of parietal pleura and the chest wall. Because of their peripheral location, adenocarcinomas may not call attention to themselves until they have developed extrathoracic metastases. For example, they may present with clinical signs of bone spread or intracranial metastatic disease.
  • Symptoms due to locoregional spread
    • These symptoms can include superior vena cava obstruction, paralysis of the recurrent laryngeal nerve, and phrenic nerve palsy, causing hoarseness and paralysis of the diaphragm; pressure on the sympathetic plexus, causing Horner syndrome; dysphagia resulting from esophageal compression; and pericardial effusion.
    • Superior sulcus tumors (Pancoast tumors) can cause compression of the brachial plexus roots as they exit the neural foramina, resulting in intense, radiating neuropathic pain in the ipsilateral upper extremity.
  • Paraneoplastic syndromes: Most paraneoplastic syndromes are caused by small cell lung cancer. However many paraneoplastic syndromes also occur in non-small cell lung cancer patients. Some examples include:
    • Squamous cell carcinomas are more likely to be associated with hypercalcemia due to parathyroid like hormone production.
    • Clubbing and hypertrophic pulmonary osteoarthropathy and Trousseau syndrome of hypercoagulability are caused more frequently by adenocarcinomas.
    • The syndrome of inappropriate antidiuretic hormone production (SIADH) is more common in small cell lung cancer but can also occur in non-small cell lung cancer.
    • Ectopic ACTH production can result in Cushing syndrome.
  • Summary of clinical characteristics by histologic subtype
    • Adenocarcinoma, arising from the bronchial mucosal glands, is the most frequent non-small cell lung cancer in the United States, representing 35-40% of all lung cancers and usually occurs in a peripheral location within the lung. Adenocarcinoma is the most common histologic subtype, and may manifest as a "scar carcinoma." This is the subtype observed most commonly in persons who do not smoke. This type may manifest as multifocal tumors in a bronchoalveolar form.
    • Bronchoalveolar carcinoma is a distinct subtype of adenocarcinoma with a classic manifestation as an interstitial lung disease on chest radiograph. Bronchoalveolar carcinoma arises from type II pneumocytes and grows along alveolar septa. This subtype may manifest as a solitary peripheral nodule, multifocal disease, or a rapidly progressing pneumonic form. A characteristic finding in persons with advanced disease is voluminous watery sputum.
    • Squamous cell carcinoma accounts for 25-30% of all lung cancers. The classic manifestation is a cavitary lesion in a proximal bronchus. This type is characterized histologically by the presence of keratin pearls and can be detected based on results from cytologic studies because it has a tendency to exfoliate. It is the type most often associated with hypercalcemia.
    • Large cell carcinoma accounts for 10-15% of lung cancers, typically manifesting as a large peripheral mass on chest radiograph. Histologically, this type has sheets of highly atypical cells with focal necrosis, with no evidence of keratinization (typical of squamous cell carcinoma) or gland formation (typical of adenocarcinomas).
    • Improved histopathologic procedures and the use of electron microscopy allow for most large cell tumors to be identified as undifferentiated adenocarcinomas and less frequently as squamous cell cancers. Large cell undifferentiated cancers have the same prognosis as do adenocarcinomas and are combined with them in clinical trials.

Physical

See the image below for a summary of all signs and symptoms.

Non–small cell lung cancer. Symptoms and si...

Non–small cell lung cancer. Symptoms and signs of lung cancer.

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Non–small cell lung cancer. Symptoms and si...

Non–small cell lung cancer. Symptoms and signs of lung cancer.


  • In approximately two thirds to three fourths of patients, the cancer is diagnosed at an advanced stage; patients may have lost weight and may have obvious respiratory distress.
  • Head and neck
    • Commonly, no signs are found upon examination of the head and neck regions, but when the cancer has spread to the supraclavicular lymph nodes, careful examination may reveal enlargement of involved nodes, which helps in the clinical staging process.
    • Superior sulcus tumors, because of their presence at the apex of the lung, can compress the cervical sympathetic plexus, causing classic Horner syndrome. Findings involve ipsilateral ptosis, miosis, enophthalmos, and anhidrosis (ie, lack of sweating).
    • The superior vena cava syndrome is commonly caused by small cell carcinomas, but any centrally located tumor or mediastinal spread can give rise to the superior vena cava syndrome. This results from obstruction of blood flow to the heart from the head and neck regions and upper extremities due to tumor compression of the superior vena cava. Patients have facial edema, dusky skin coloration, and, possibly, conjunctival edema. Edema of the upper extremities and prominent veins on the upper thoracic wall with retrograde flow may be present.
  • Respiratory system
    • Findings are variable and depend on location and spread.
    • Centrally located obstructing tumors can cause collapse of the entire lung with an absence of breath sounds on the side of the lesion.
    • Peripheral lesions can cause individual segments or lobes to collapse, leading to findings of dullness to percussion and/or decreased breath sounds.
    • Pleural effusions give rise to characteristic findings of dullness and decreased breath sounds, depending on the size.
  • Cardiovascular system: Cardiac findings are usually noted when the tumor causes an effusion. Findings can range from simple effusion to tamponade. Direct cardiac involvement may also occur.
  • Gastrointestinal system: The most common site of metastatic spread is the liver, which may manifest as tender hepatomegaly.
  • Musculoskeletal system
    • Bone is another common site of spread for lung carcinomas.
    • Patients may report bone pain, and tender spots may be found during examination.
    • The examination should include fist percussion of the spine to look for tender spots, which may suggest vertebral column metastases.
  • Central nervous system: A neurologic examination should be performed to look for focal neurological deficits caused by brain metastases and/or signs of spinal cord compression.

Causes

  • Smoking
    • Unlike many other malignancies, whose causes are largely unknown, the cause of lung cancer is tobacco smoking in as many as 90% of patients (78% in men, 90% in women).
    • Tobacco smoke contains more than 300 harmful substances with at least 40 known potent carcinogens. Poly-aromatic hydrocarbons and the nitrosamine-NNK are known to cause DNA damage by forming DNA adducts in animal models. Benzo-A-pyrine also appears to induce molecular signaling such as AKT as well as inducing mutations in p53 and other tumor suppressor genes.   
    • The development of lung cancer is directly related to number of cigarettes smoked, length of smoking history, and the tar and nicotine content of the cigarettes, and are highest among current smokers and lowest among nonsmokers. A large trial showed that persistent smokers had a 16-fold elevated lung cancer risk, which was further doubled in those who started smoking when younger than 16 years. The age-adjusted incidence rates range from 4.8-20.8 per 100,000 among nonsmokers to 140-362 among active smokers.
    • The risk of lung cancer declines slowly after smoking cessation. Long-term follow-up studies show that the relative risk remains high in the first 10 years after cessation and gradually declines to 2 approximately 30 years after cessation. This long-term risk explains the development of almost 50% of United States lung cancer cases in past smokers.
    • Smoking prevalence in the United States has gradually declined over last 4 decades. In 2005, an estimated 45 million active smokers were in the United States, with highest prevalence among Native Americans and lowest prevalence among Hispanic and Asian Americans. Worldwide, the incidence of smoking in developing countries is on the rise, with almost 320 million smokers in China alone.
    • Because not all persons who smoke develop lung cancer and because not all patients with lung cancer have a history of smoking, other factors, including genetic susceptibility, also play a causative role.
  • Passive smoking
    • As many as 25% of the lung cancers in persons who do not smoke are believed to be caused by secondhand smoke.3 The US Environmental Protection Agency recently recognized passive smoking as a potential carcinogen. About 3000 cases of lung cancer appear to be related to passive exposure. This awareness has led to local ordinances restricting smoking in enclosed public places including restaurants and government buildings.
    • Cigarette smoke containing the carcinogenic N -nitrosamines and aromatic polycyclic hydrocarbons can be inhaled passively by nonsmokers. Urinary levels of these carcinogens are 1-5% of those found in active smokers.
  • Asbestos
    • Asbestos exposure has been shown to be strongly associated with the causation of lung cancer, malignant pleural mesothelioma, and pulmonary fibrosis.
    • The silicate type of asbestos fiber is an important carcinogen.
    • Asbestos exposure increases the risk of developing lung cancer by as much as 5 times.
    • Tobacco smoke and asbestos exposure act synergistically, and the risk of developing lung cancer for persons who currently smoke tobacco and have a history of asbestos exposure approaches 80-90 times that of control populations.
  • Radon
    • Radon is an inert gas produced as a result of uranium decay. Radon exposure is a well-established risk factor for lung cancer in uranium miners. Approximately 2-3% of lung cancers annually are estimated to be caused by radon exposure.
    • The US National Research Council's report of the Sixth Committee on Biological Effects of Ionizing Radiation has estimated that radon exposure causes 2100 new lung cancers each year, while it contributes to lung cancer causation in approximately 9100 persons who smoke.
    • Household exposure to radon has never been clearly shown to cause lung cancer.
  • HIV infection: A recent report from the State of Texas Health Department suggested a 6.5-fold increase in lung cancer in patients infected with HIV. Other large series do not support an increased prevalence of lung cancers in subjects with HIV infection.4,5
  • Other environmental agents
    • Beryllium, nickel, copper, chromium, and cadmium have all been implicated in causing lung cancer.
    • Dietary fiber and vegetables have been suggested as protective from lung cancer.
    • In a recent study, alpha-tocopherol and carotenoids have been found to be harmful rather than beneficial in decreasing the mortality from lung cancer.

More on Lung Cancer, Non-Small Cell

Overview: Lung Cancer, Non-Small Cell
Differential Diagnoses & Workup: Lung Cancer, Non-Small Cell
Treatment & Medication: Lung Cancer, Non-Small Cell
Follow-up: Lung Cancer, Non-Small Cell
Multimedia: Lung Cancer, Non-Small Cell
References
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Further Reading

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Keywords

bronchogenic carcinoma, NSCLC, non-small cell lung cancer, non-small-cell lung cancer, nonsmall cell lung cancer, adenocarcinoma, squamous cell carcinoma, SCC, lung SCC, large cell carcinoma, bronchoalveolar carcinoma, broncho-alveolar carcinoma, lung carcinoma, lung malignancy, tobacco, smoking, asbestos, radon, secondhand smoke, passive smoking, second-hand smoke, smoking-related cancer, lung cancer

acinar adenocarcinoma, papillary adenocarcinoma, bronchoalveolar adenocarcinoma, mucus-secreting adenocarcinoma, large cell neuroendocrine carcinoma, lobectomy, pneumonectomy, ras oncogene, H-ras, K-ras, N-ras, c-myc, c-raf, ectopic hormone production, atelectasis, postobstructive pneumonia, wheezing, hemoptysis, pleural effusion, superior vena cava obstruction, superior vena cava syndrome, paralysis of recurrent laryngeal nerve, phrenic nerve palsy, paralysis of the diaphragm, Horner syndrome, dysphagia, esophageal compression, pericardial effusion, Pancoast tumor, paraneoplastic syndromes, hypercalcemia, clubbing, hypertrophic pulmonary osteoarthropathy, Trousseau syndrome of hypercoagulability, scar carcinoma, gynecomastia, galactorrhea, spinal cord compression, silicate type of asbestos, HIV infection, diesel exhaust

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Contributor Information and Disclosures

Author

Syed Huq, MD, Fellow, Division of Hematology-Oncology, Department of Internal Medicine, University of Missouri-Columbia School of Medicine, Ellis Fischel Cancer Center
Syed Huq, MD is a member of the following medical societies: American Medical Informatics Association, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia
Irfan Maghfoor, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Antoni Ribas, MD, Assistant Professor of Medicine, Division of Hematology-Oncology, University of California at Los Angeles Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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