CHAPTER 70

Carcinoma of the Lung

Sonai Bordia, MD • Nay Min Tun, MD

Lung cancer is the second most common cancer in both sexes and the leading cause of cancer deaths in the United States, killing nearly three times as many men as prostate cancer and about twice as many women as breast cancer. Age-adjusted lung cancer death rates are 68.8 per 100,000 men and 40.6 per 100,000 women in the United States (Kohler et al., 2011). Given the magnitude of the problem, it is incumbent upon every primary care provider to have a good knowledge of lung cancer and its management. The most important aspects of epidemiology, diagnosis, treatment, and prevention are reviewed here.

ANATOMY, PHYSIOLOGY, AND PATHOLOGY

The term lung cancer refers to carcinoma arising from the respiratory epithelium (bronchi, bronchioles, and alveoli). The four basic histologic types of lung cancer are adenocarcinoma, squamous cell carcinoma, small-cell carcinoma, and large-cell carcinoma. A widely used classification divides lung cancer into two major groups: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), reflecting the different natural histories and therapeutic approaches. NSCLC accounts for approximately 85% of all lung carcinoma. Adenocarcinoma is the most common type of NSCLC, followed by squamous cell carcinoma, and other histologic types.

Small-cell carcinoma is a poorly differentiated neuroendocrine tumor. The cells have scant cytoplasm, hyperchromatic nuclei with a fine (“salt and pepper”) chromatin distribution, and prominent nuclei. It tends to occur centrally with endobronchial growth and is strongly associated with smoking. SCLC, more often than NSCLC, may cause paraneoplastic syndromes by producing specific peptide hormones such as adrenocorticotrophic hormone (ACTH), arginine vasopressin (AVP), and atrial natriuretic peptide (ANP).

Squamous cell carcinomas arise from bronchial epithelial cells where squamous metaplasia is present. The histologic hallmarks of these tumors include keratin “onion pearls” and intercellular bridges. This cell type is classically associated with a history of smoking. Because of identical morphology, it requires clinical correlation to differentiate squamous cell carcinoma of the lung from head and neck squamous cell carcinoma. Like SCLC, squamous cell carcinoma of the lung tends to occur centrally, and present with chronic cough, hemoptysis, or obstructive atelectasis. Because of their central location, sputum cytology is more likely to be positive. Squamous cell carcinoma is most often associated with hypercalcemia attributed to production of parathyroid hormone-like peptide.

Adenocarcinomas, in contrast, tend to occur in the periphery of the lung rather than the central airways. Although tobacco use may be associated with adenocarcinomas, they are the most common type of lung cancer occurring in “never smokers.” The tumor may show glandular formation, papillary growth, bronchoalveolar pattern, or cellular mucin. Invasive adenocarcinoma with bronchoalveolar features (previously known as bronchoalveolar carcinoma) is a subtype of adenocarcinoma that originates in the terminal bronchioles and extends into the alveolar spaces. Radiologically, it may present as a diffuse multinodular lesion, as a pneumonic infiltrate, and on screening CT scans as a ground-glass opacity. Adenocarcinomas are more likely to metastasize to extrapulmonary sites than are squamous cell carcinomas. After complete resection of an intrathoracic tumor, distant metastasis to the bone, brain, liver, or adrenals is the most frequent pattern of recurrence. Because of their peripheral location, they are less likely to cause symptoms early in their development.

EPIDEMIOLOGY

The incidence of lung cancer correlates with the prevalence of cigarette smoking. Among plausible etiologic factors, cigarette smoking continues to be the major cause of lung cancer. The relative risk of lung cancer in a long-term smoker is 10 to 30 times that of a never smoker. Cigarette smoking increases the risks of all the major lung cancer cell types (Khuder, Dayal, Mutgi, Willey, & Dayal, 1998). Cigar and pipe smoking increase the risk of lung cancer to a lesser degree compared to cigarette smoking. Environmental tobacco smoke or secondhand smoke is also an established cause of lung cancer. The risk for developing lung cancer is directly related to the number of cigarettes smoked daily, years of use, depth of inhalation, cigarette tar content, use of filterless cigarettes, and age of smoking onset. Although the risk is significantly reduced by smoking cessation, it never reaches that of never smokers.

In addition to tobacco smoking, exposure to potential carcinogens in the workplace or environment increases the risk for the development of lung cancer. Some of these carcinogens are ionizing radiation, asbestos, arsenic, vinyl chloride, nickel, chromium, beryllium, and polycyclic aromatic hydrocarbons. All of these can act as cocarcinogens with tobacco smoke, and the risk for lung cancer in exposed smokers is multiplicative.

Radon produces alpha particles and is directly carcinogenic to the respiratory epithelium. It also acts as a cocarcinogen with tobacco smoke. All homes contain some radon; the concentrations are highest in the basement and lower floors. A population-based study found that long-term residents in a home with mean radon concentrations above the U.S. Environmental Protection Agency (EPA) guideline value (148 Bq/m³) experienced a 34% increase in risk for lung cancer mortality relative to those below the guideline value. In addition, a 15% increase in the risk of lung cancer mortality was observed per 100 Bq/m³ increase in radon concentration (Turner et al., 2011).

Preexisting lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis independently increase the risk for the development of lung cancer. Poor clearance of potential carcinogens is the probable mechanism in chronic obstructive lung disease. Persistent chronic inflammation in diseases leading to pulmonary fibrosis is likely to be associated with the increased incidence of lung cancer.

The risk of lung cancer seems to be higher among individuals with low fruit and vegetable intake. However, chemoprevention clinical trials failed to show the beneficial effects of supplementation with retinoids and carotenoids. Rather, they might increase the risk of lung cancer (Satia, Littman, Slatore, Galanko, & White, 2009).

Lung cancer is rare before 40 years of age, with rates increasing until 80 years, after which the rate reduces. The overall incidence of lung cancer in the United States is 70 cases per 100,000 population. There are well-recognized racial, sex, and geographic differences. For males, the incidence is higher in African Americans than in Whites. For females, the reverse is true. Asians and Hispanics have a much lower incidence (Kohler et al., 2011).

DIAGNOSTIC CRITERIA

The definitive diagnosis of lung cancer requires the identification of malignant cells in a cytologic specimen (sputum, bronchial washing, bronchial brushing, bronchoalveolar lavage, transbronchial, and transthoracic needle aspirates or pleural fluid), or the detection of areas of malignant transformation in a biopsy specimen from the transthoracic, endobronchial, transbronchial, or open biopsy procedures.

Clinical Pearls

After histological diagnosis of lung cancer is made, it is important for providers to order epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement testing at the time of diagnosis for patients with advanced-stage lung adenocarcinoma, regardless of their clinical history, because these patients will benefit from targeted drugs matched to these biomarkers (Lindeman et al., 2013).

In the United States, up to 20% of patients with lung adenocarcinoma, the most common type of lung cancer, will test positive for one of the two biomarkers.

The prototypical lung cancer patient is a current or former smoker, usually in the seventh decade of life. Lung cancer should be suspected in any patient presenting with a lung nodule or mass on chest x-ray, even in the absence of any symptoms, or when a pneumonia fails to resolve radiologically in 6 to 8 weeks after appropriate antibiotic therapy, especially in a patient with a history of tobacco use. Lung cancer should always be suspected in a current or former smoker who presents with chronic cough, especially when complicated by hemoptysis, even in the face of a normal chest x-ray.

HISTORY AND PHYSICAL EXAMINATION

Although as many as 15% of lung cancer patients are asymptomatic at the time of diagnosis, the early symptoms are nonspecific and are often ignored for prolonged periods. More than half of all patients diagnosed with lung cancer present with advanced disease at the time of diagnosis.

The clinical presentation of lung cancer is diverse. Symptoms and signs can be attributed to the following:

Local tumor growth, invasion, or obstruction

Regional tumor spread to lymph nodes and adjacent structures

Extrathoracic distant metastatic spread

Paraneoplastic syndromes

Clinical manifestations, in order of decreasing frequency, are cough, weight loss, dyspnea, chest pain, hemoptysis, bone pain, clubbing, fever, weakness, superior vena cava obstruction, dysphagia, and wheezing and stridor. Some patients may initially present with laboratory abnormalities such as elevated alkaline phosphatase, elevated liver enzymes, and hypercalcemia.

Symptoms arising from local tumor growth depend on the location and size of the tumor. Central or endobronchial growth of the primary tumor is more likely to be associated with cough early on, and ultimately may lead to hemoptysis. Hemoptysis, when present, is the most alarming symptom to patients, and they usually seek medical attention expeditiously. Critical narrowing of a bronchus by endobronchial tumor or by extrinsic compression may lead to all the symptoms associated with postobstructive pneumonitis (e.g., fever, dyspnea, wheezing). Peripheral growth of the primary tumor is more frequently associated with cough and pain from involvement of the pleura or chest wall.

Regional spread of tumor in the thorax (direct extension of the tumor or metastasis to regional lymph nodes) may be associated with dysphagia from esophageal compression, stridor from tracheal obstruction, hoarseness of the voice from recurrent laryngeal nerve paralysis, and dyspnea and hemidiaphragmatic elevation from phrenic nerve paralysis. Apical (superior sulcus) tumors may cause Pancoast’s syndrome (shoulder pain radiating in the ulnar nerve distribution of the arm, atrophy of hand muscles and Horner’s syndrome) due to involvement of the eighth cervical and first and second thoracic nerve roots and the brachial plexus.

Superior vena cava obstruction as a result of compression or direct invasion by the tumor itself or by enlarged mediastinal lymph nodes may cause headache, facial fullness, and dyspnea. Physical examination may reveal facial and upper-extremity swelling with plethora, dilated neck veins, and elevated jugular venous pressure with loss of waveforms. Spread to pericardium and heart may cause pericardial effusion/tamponade, arrhythmia, or heart failure. Involvement of pleura results in pleural effusion, whereas lymphangitic spread leads to hypoxemia and dyspnea. Moreover, some types of lung cancer can grow transbronchially along multiple alveolar surfaces, with resultant impairment of gas exchange, hypoxemia, dyspnea, and sputum production.

Bone metastasis commonly involves the vertebrae, ribs, and pelvic bones. It may present with pain, pathologic fractures, or cord compression. Bone marrow infiltration by cancer cells may cause cytopenias or leukoerythroblastosis. Patients with liver metastases may present with hepatomegaly and right upper quadrant abdominal pain, as well as nonspecific symptoms of fatigue, anorexia, and weight loss. Brain metastases can be associated with headache, nausea and vomiting, seizures, confusion, personality changes, and focal neurologic signs and symptoms, depending on the site of metastatic disease. Adrenal metastases are common but rarely cause pain or adrenal insufficiency.

Not infrequently, the initial clinical manifestations may be secondary to paraneoplastic syndromes associated with lung cancer (Thomas, Kwok, & Edelman, 2004). Paraneoplastic syndromes occur in approximately 10% to 20% of patients with lung cancer, especially those with SCLC. A list of the paraneoplastic syndromes associated with lung cancer is provided in Table 70.1. Paraneoplastic syndromes may mimic metastatic disease and, if not detected, may lead to inappropriate palliative rather than curative therapy. Paraneoplastic syndromes often resolve with successful treatment of the primary tumor.

The physical examination findings are variable and depend on the extent of locoregional spread, and the presence of distant metastases and paraneoplastic syndromes. The lung examination may be completely normal, even when there is radiologic evidence of tumor. Centrally located (endobronchial) tumors are likely to cause symptoms earlier. The primary care provider may appreciate decreased air entry to a particular lung segment or high-pitched inspiratory sounds over the involved bronchus. Large pleural effusions may also result in compressive atelectasis, along with all the expected physical examination findings (e.g., decreased air entry, bronchial breathing, dullness to percussion). The presence of supraclavicular or cervical adenopathy is an important clinical finding and implies advanced inoperable disease.

The presence of significant jugular venous distention suggests involvement of the superior vena cava or pericardial carcinomatosis. All the signs of cardiac tamponade may be seen (e.g., tachycardia, narrow pulse pressure, pulsus paradoxus, faint heart sounds, enlarged cardiac silhouette), and they should prompt an urgent request for echocardiography, followed by pericardiocentesis or pericardial window. Funduscopic evidence of papilledema, even in the absence of symptoms, should lead to the performance of cranial CT or MRI to rule out brain metastases. A variety of neurologic findings may be detected on physical examination, depending on the level of involvement and the presence of paraneo-plastic syndromes.

DIAGNOSTIC STUDIES

The chest x-ray is the initial diagnostic tool for lung cancer. Radiologic presentation of lung cancer is diverse and includes:

Completely normal studies (with small endobronchial lesions)

An isolated pulmonary nodule (peripheral, <2 cm, and completely surrounded by lung parenchyma)

A large mass lesion, either surrounded completely by lung or abutting and invading the chest wall or mediastinum

Cavitary lesion secondary to central tumor necrosis (most often associated with squamous cell carcinoma)

Obstructive atelectasis with signs of volume loss (mediastinal or cardiac silhouette shift to the side of atelectasis and ipsilateral elevation of the hemidiaphragm)