Epidemiology and Etiology

Lung cancer is the leading cause of cancer mortality for men and women, exceeding the mortality of breast, colon, and prostate cancer combined.¹ In the United States, more than 219,000 new cases of lung cancer and 159,000 deaths were anticipated in 2009.¹

The epidemiologic data on smoking and lung cancer fulfill the criteria for causal association, including the consistency of results across studies, the strength of relationship, its specificity, the correct temporal sequence between exposure and disease, and the coherence of the association as evidenced by a dose-response relationship.² It is estimated that cigarette smoking is the cause of 90% of all lung cancers.³ Multiple genetic alterations of tumor suppressor genes and oncogenes can lead to the pathogenesis of lung cancer. Carcinogens in cigarette smoke are involved in these genetic alterations, mainly through the formation of deoxyribonucleic acid (DNA) adducts.⁴ There is a clear dose-response relationship between the risk of lung cancer and the number of cigarettes smoked per day, the degree of inhalation, and the age at initiation of smoking.⁵ The relative risk of developing lung cancer decreases as the time from cessation increases.⁵

Approximately 10% of lung cancers are thought to be caused by carcinogens other than cigarette smoking. Among nonsmokers, 30% of lung cancer deaths are attributed to radon exposure.³ Increases in lung cancer risk also accompany exposure to carcinogens such as asbestos, bis(chloromethyl) ether, polycyclic aromatic hydrocarbons, chromium, nickel and inorganic arsenic compounds.⁶^,⁷ The association with occupational exposure to these agents appears to be independent of cigarette smoking. In addition, a number of occupations with high smoking prevalence have increased cancer risk. Women who work as waitresses, cashiers, nurses’ aides, and orderlies have smoking prevalences in excess of 40%, as do men who work as drivers, construction workers, painters, mechanics, and watchmen.⁸

Chemoprevention strategies have failed to demonstrate the ability to reduce the risk of developing lung cancer. Epidemiologic and case control trials previously reported an inverse relationship between the incidence of lung cancer and the intake of many food groups, including dietary carotenoids such as beta-carotene and lycopene.⁹ The mechanism of this interaction was theorized to be related to scavenging of free radicals or through antioxidative effects. However, the Beta-Carotene and Retinol Efficacy Trial (CARET), which included more than 18,000 participants, found that supplementation with betacarotene actually increased the risk of developing lung cancer by 12% versus patients who received placebo, and even increased all-cause mortality by 8%.¹⁰ Likewise, the retinoid isotretinoin was ineffective in reducing the development of second primary tumors in 1166 patients with prior stage I non–small cell lung cancer (NSCLC), and even increased the risk of death for active smokers.¹¹

Anatomy

The external anatomy of the lung is dominated by the fissures and the concave cardiac notch on each lung. On both the left and the right lung, the oblique fissure extends from the surface of the lung to the hilum and divides the lung into upper and lower lobes, which are connected only by the lobar bronchi and vessels. On the right lung, a horizontal fissure passes from the anterior margin into the oblique fissure to separate the wedge-shaped middle lobe from the upper lobe. This separation is incomplete in most patients. The visceral pleura covering the surface of the lung extends inward to line the depths of the fissures. The trachea divides into a left and right main stem bronchus at the carina. The right main stem bronchus (approximately 4.5 cm long) gives off a right upper lobe bronchus and continues as the bronchus intermedius, which separates into middle- and lower-lobe bronchi. The left main stem bronchus gives off three branches, but the upper and middle ones are fused before they separate into the upper lobe and lingular lobe. The other branch is the lower-lobe bronchus. Each lobar bronchus in turn gives off segmental bronchi totaling 10 segments on each side of the lung.

Pathogenesis and Histologic Findings

Pathogenesis

There is increasing evidence that lung cancer is derived from a pluripotent stem cell that is capable of expressing a variety of phenotypes. This epithelial stem cell, in normal histogenesis, differentiates into those cells found in the tracheobronchial tree, including pseudostratified reserved cells, ciliated goblet columnar cells, and neuroendocrine cells as type I and II pneumocytes seen lining the alveoli. Those cells that are capable of division can express hyperplastic, metaplastic, or neoplastic change. Lung cancer may exhibit two or more histologic patterns; the frequency of this occurrence may depend of the number of sections examined. In one study, when at least 10 blocks from each tumor were examined, 45 of the 100 cases showed elements of both squamous cell carcinoma and adenocarcinoma.¹²

Squamous Cell Carcinoma

Squamous cell carcinoma arises most frequently in proximal bronchi and is associated with squamous metaplasia and carcinoma in situ. Histologically, the squamous cell tumor is composed of sheets of epithelial cells that may be well- or poorly differentiated. Most well-differentiated tumors demonstrate keratin pearl formation. The more poorly differentiated tumors, if determined to be squamous cell carcinomas, have positive keratin staining.

Adenocarcinoma

Adenocarcinoma is now the most frequent tumor, accounting for 40% of all lung cancer. Some of this increase is due to better identification of adenocarcinoma, with fewer tumors being classified as undifferentiated large cell tumors. The majority of these tumors are peripheral in origin, arising from surface epithelium or bronchial mucosal glands and can also be seen arising as peripheral scar tumors. Histologically, these tumors form glands, and produce mucin. Bronchoalveolar carcinomas arise from type II pneumocytes, and grow along alveolar septa showing little desmoplastic or glandular change. These tumors may present in three different fashions: a solitary peripheral nodule, multifocal disease, or a progressive pneumonic form that appears to spread from lobe to lobe, ultimately encompassing both lungs.

Large Cell Carcinoma

Large cell carcinoma is the least common of all NSCLCs, accounting for approximately 15% of all lung cancers. Using histochemical staining, electron microscopy, and monoclonal antibodies, many tumors, previously diagnosed as undifferentiated large cell carcinoma, can now be classified more appropriately as poorly differentiated adenocarcinoma or squamous cell carcinoma. For this reason, the incidence of this type of tumor continues to decrease.

Immunohistochemistry

Thyroid transcription factor 1 (TTF-1) is frequently expressed in lung cancers, especially adenocarcinomas and small cell lung cancers (SCLCs). It is helpful in distinguishing lung cancers from other thoracic malignancies.

Clinical Presentation

The signs and symptoms manifested by patients suffering from lung cancer depend on the location of the tumor, its locoregional spread, and the effects of metastatic growth. Common presenting complaints resulting from the pulmonary mass include shortness of breath, cough, hemoptysis, or chest pain. However, a high proportion of patients have symptoms related to metastatic disease at presentation, including bone pain caused by osseous metastases or neurologic symptoms caused by brain metastases. Lung cancer is also frequently associated with paraneoplastic syndromes. In addition, many patients have constitutional symptoms such as anorexia, weight loss, and a decline in performance status at diagnosis. Some patients present with an asymptomatic lesion discovered incidentally on a chest x-ray examination.

Routine screening for lung cancer is being investigated once again. Prior trials conducted in the 1970s failed to show any benefit for the use of chest x-ray examination to screen smokers for lung cancer. More recent studies, however, are exploring the use of computed tomography (CT) scans for screening because they can detect smaller lung nodules. The Early Lung Cancer Action Project was a pilot study of 1000 patients older than the age of 60 with greater than 10 pack-years of smoking who underwent routine screening with low-dose thoracic CT scans. It found almost four times as many cancers as chest x-ray examination alone and these lesions were six times as likely to be early stage and therefore more curable.¹³ A follow-up study, the International Early Lung Cancer Action Project screened 31,567 asymptomatic persons at risk for lung cancer from 1993 through 2005.¹⁴ Of these, 27,456 had repeat screenings 7 to 18 months later. Of the 31,567 participants, 484 were diagnosed with lung cancer, 85% of whom were clinical stage I. The estimated survival in this subgroup was 88%. Other groups have concluded that screening increases the rate of lung cancer diagnosis and treatment, but doesn’t reduce the risk of advanced lung cancer or death from lung cancer.¹⁵ Currently, a large national trial is underway to rigorously assess the benefit of screening in this population.

Diagnostic and Staging Procedures

History and Physical Examination

A detailed history should elicit tobacco use and past exposure to environmental carcinogens that may suggest a higher probability of lung cancer. Symptoms of metastatic disease in the bone and brain can also be determined. Weight loss of greater than 5% from baseline is one of the most important prognostic indicators in lung cancer treatment. Patients can present with signs and symptoms of paraneoplastic syndromes, more frequently in SCLC than NSCLC.

Physical examination of the chest may detect signs of partial or complete obstruction of airways, atelectasis, pneumonia, or pleural effusion. Examination of the neck can reveal evidence of supraclavicular lymphadenopathy, indicative of N₃ disease. Lymphadenopathy in the high neck or axilla may represent metastatic disease. Abdominal examination may detect hepatomegaly. Neurologic examination can detect cerebral, base-of-skull, or spinal cord metastases.

Laboratory studies should include complete blood count, liver function tests, and serum lactate dehydrogenase (LDH). Elevated alkaline phosphatase may indicate liver or bone disease. Renal function tests should be performed to assess whether the patient can tolerate intravenous contrast for radiologic examinations and certain types of chemotherapy.

Imaging Studies

Chest x-ray examination remains an extremely valuable tool in the diagnosis of lung cancer. However, CT scan has enormous advantages in its ability to detect lesions that cannot be visualized on chest x-ray examination. It also plays an important role in staging lung cancer, especially spread to areas of the mediastinum undetected on plain films. Typically, a lymph node is considered normal if it is less than 1 cm in diameter on its short axis. CT may also suggest possible areas of local invasion of the primary tumor to the chest wall, vertebrae, or mediastinal structures. Small pleural effusions or pleural nodules, often undetected on plain films, may be evident on CT. A CT of the chest for lung cancer evaluation should also include part of the upper abdomen, which allows for evaluation of the liver and adrenals for metastatic disease. Scanning with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning can also detect neoplastic activity. Studies have shown CT and PET to be more specific and sensitive than PET alone.¹⁶ Generally, the sensitivity, specificity, and accuracy of CT scan alone is approximately 70%. CT and PET together have an accuracy of approximately 90% in single-institution studies, although these results may worsen when the technique is studied across multiple institutions. Magnetic resonance imaging (MRI) has not been shown to be more effective than chest CT for lung tumor, but may be helpful to evaluate invasion of vertebral bodies in the mediastinum.

Sputum Cytologic Examination

With three sputum samples, up to 80% of central tumors can be diagnosed. The yield is much smaller for peripheral tumors and drops to less than 20% for peripheral tumors less than 3 cm in diameter.

Bronchoscopy

Using flexible fiberoptic instruments, the proximal tracheobronchial tree can be examined up to the second or third subsegmental subdivision and cytologic or histologic specimens can be obtained. When a visible lesion is identified, the diagnostic yield is much more than 90%. Even with no visible lesion, the area of suspicion can be irrigated and lavaged to obtain cytologic material. Using fiberoptic bronchoscopy and image intensification, peripheral lesions can be reached by cytology brushes, needles, or biopsy forceps and specimens can be obtained. This is especially effective for lesions larger than 2 cm in diameter. The bronchoscope is also a valuable tool for staging. The site of a primary tumor in a major airway may affect its T stage, and transbronchoscopic needle aspiration through its airway wall can confirm the presence of a malignancy in mediastinal lymph nodes.

Endobronchial ultrasonography allows detailed imaging of the bronchial wall and peribronchial mediastinum, and may also add to the evaluation of endobronchial lesions.¹⁷

Endobronchial ultrasound-guided biopsy of mediastinal and hilar lymph nodes is becoming more commonly employed in the staging of lung cancer. Yields of this technique are approximately 95% with minimal to no severe toxicity.¹⁸

Mediastinoscopy and Mediastinotomy

Mediastinoscopy is the most accurate technique to assess superior mediastinal lymph nodes, which are frequently involved in NSCLC. The procedure is simple, safe, and effective in experienced hands. In one large series, the complication rate from cervical mediastinoscopy was 2.3% and the mortality was 0%.¹⁹ In patients suspected of having inoperable disease by virtue of mediastinal involvement as detected by CT scanning, confirmation by mediastinoscopy is indicated. For patients who are potentially operable, it is especially important to sample contralateral mediastinal lymph nodes to determine if N₃ disease is present. Involvement of aorticopulmonary lymph nodes are typically assessed by anterior mediastinotomy (Chamberlain procedure).²⁰ It is important to remember that these are first-echelon mediastinal lymph nodes for left lung tumors, especially from the left upper lobe, and they may not be sampled when a cervical mediastinoscopy is performed.

Thoracoscopy

Video-assisted thoracoscopy has been used in the diagnosis and staging of NSCLC. Peripheral nodules can be identified and biopsied or excised using video-assisted techniques and mediastinal lymph nodes can be sampled for histologic examination. This technique can identify suspected pleural disease and has the ability to accurately assess the status of pleural effusions.

Staging of Lung Cancer

In 1997, the sixth edition of the tumor-node-metastasis (TNM) staging system for NSCLC was published.²¹ Some criticisms of the staging included that the sample size was relatively small, the data was from few institutions, the staging was mostly surgical, modern imaging was not incorporated into the staging, and there was minimal external validation. In an attempt to improve on these shortcomings, the International Association for the Study of Lung Cancer (IASLC) revised the TNM staging system in 2009.

There are a number of changes from the sixth edition. T₁ tumors have been subclassified by size into T_1a (≤2 cm) and T_1b (>2-3 cm). T₂ tumors have been subclassified into T_2a (>3-5 cm) and T_2b (>5-7 cm). T₃ classification now includes tumors greater than 7 cm (previously T₂ tumors). Two nodules in the same lobe are now classified as T₃ (previously T₄). An ipsilateral lung tumor is now T₄ (previously M₁). Malignant pleural effusions, which were generally treated in the same manner as metastatic disease, are now classified as M_1a (previously T₄