Definition and Epidemiology

Lung cancer, also referred to as bronchogenic carcinoma, encompasses multiple malignancies involving the lung or airways. The vast majority of lung cancers are categorized as non–small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) based on the histologic characteristics.

Although lung cancer was notably uncommon near the turn of the 20th century, increased exposure to tobacco smoke has caused a global epidemic of lung cancer.¹ In 2015 there were projected to be an estimated 221,200 new cases of lung cancer and 158,040 deaths in the United States.² Although recently there has been a slight decline in the incidence of lung cancer within the United States, lung cancer remains the leading cause of cancer death among both males and females in this country. The 5-year survival rate for lung cancer as a whole is less than 20%.¹ The primary risk factor for lung cancer is smoking tobacco which accounts for 80% to 90% of cases.³ Other risk factors include secondhand smoke, air pollution, radon, ionizing radiation, a family history of lung cancer, and occupational exposures such as asbestos, tar, and soot.⁴

Pathophysiology

NSCLC represents approximately 85% of lung malignancies. The primary subtypes of NSCLC are adenocarcinoma (50%) and squamous cell carcinoma (25%), with the remainder consisting of large cell carcinomas and other less common variants.⁵ Historically, these histologic subtypes have been grouped together as NSCLC and managed in a similar fashion, although there are some treatment considerations based on histology. SCLC comprises approximately 13% of lung cancers. Although smoking is linked with all forms of lung cancer, it is most strongly associated with SCLC and squamous cell carcinoma. Adenocarcinoma is the most common type of lung cancer in nonsmokers.

The precise path that causes the malignant transformation of bronchoepithelial cells is not fully understood. Smoking tobacco is the primary cause in the vast majority of lung cancers. Yet, only approximately 10% of smokers will develop lung cancer, which points to significant host factors that may control an individual’s susceptibility to cancer.⁶ Carcinogens such as tobacco smoke, radon, and asbestos fibers induce tissue injury with resultant genetic and epigenetic changes. Over time these changes cause various pathways that control cellular proliferation to become dysregulated, which ultimately leads to tumor formation, invasion, and metastasis.⁷ Individuals have varying inherent genetic susceptibility to these carcinogens, and epidemiologic studies suggest there can be a familial predisposition to lung cancer independent of tobacco smoke exposure.¹ More recently, specific acquired genetic abnormalities in non–small cell lung tumors have been identified that have significant clinical implications. The two most important of these acquired abnormalities are the epidermal growth factor receptor (EGFR) gene mutations and the anaplastic lymphoma kinase (ALK) gene rearrangements. EGFR mutations are present in approximately 15% of adenocarcinomas in the United States and are more commonly seen in nonsmokers, females, and individuals of Asian descent. EGFR mutations are found in 35% of lung cancers in Asia. ALK rearrangements are identified in approximately 4% of adenocarcinomas in the United States, most frequently in nonsmokers and younger patients. As discussed later, specific therapies targeting these molecular defects have been developed with encouraging results.¹ Tumor specimens are now routinely being tested for these abnormalities. Other so-called driver mutations have also been identified in lung cancer (e.g., ROS1, BRAF), and efforts to develop additional targeted treatment agents are under way. Although SCLC cells also have characteristic mutations (e.g., loss of function of the tumor-suppressor retinoblastoma gene RB1, or p53 mutations), these have not yet resulted in targeted therapies.⁸

Clinical Presentation and Physical Examination

The typical lung cancer patient will be a current or former smoker in the seventh or eighth decade of life. At diagnosis, only approximately 15% of lung cancers are confined to the lung. Twenty-two percent have spread to regional lymph nodes, and nearly 60% have already metastasized. The majority of patients with lung cancer are symptomatic at presentation. Cough (up to 75% of cases), weight loss (up to 68%), and dyspnea (up to 60%) are the most common presenting signs and symptoms.⁹ Cough is particularly seen with squamous cell carcinomas and small cell carcinomas owing to their tendency to involve central airways, whereas adenocarcinomas are more often peripherally located. Although cough is common in a smoking population in general, changes in a chronic cough should prompt consideration of malignancy. Other frequent presentations involve chest pain or discomfort and hemoptysis. Recurrent pneumonias in a similar anatomic area may indicate a neoplasm causing postobstructive changes, and further investigation is warranted. In addition, as with other malignancies, lung cancer is a hypercoagulable state, and patients may have deep vein thrombosis on presentation.

Although lung cancer can spread to any organ, the most common sites of metastasis are the liver, bones, adrenal glands, and brain. About a third of patients will have symptoms caused by distant metastasis at presentation. Weight loss of more than 10 pounds, focal skeletal pain (from bone metastases), or neurologic complaints such as headache or extremity weakness (from brain metastases) are the symptoms that most commonly indicate the presence of metastatic disease.⁹ Patients with lung cancer often have abnormal blood counts with anemia, leukocytosis, and thrombocytosis. A hematocrit of less than 40% in males and 35% in females or an elevated calcium or γ-glutamyl transpeptidase (GGT) level also increases the likelihood of metastatic disease. On physical examination, the signs that most commonly indicate metastatic disease are palpable lymphadenopathy greater than 1 cm, bone tenderness, hepatomegaly, focal neurologic findings, or a soft tissue mass.⁹

Many of the signs and symptoms of SCLC and NSCLC are similar, but SCLC symptoms tend to progress more rapidly, typically over 8 to 12 weeks. NSCLC has a slower tempo, with tumor growth typically seen over many months. SCLC is also more frequently associated with paraneoplastic syndromes, with the most common entity, the syndrome of inappropriate antidiuretic hormone secretion (SIADH), seen in 15% to 40% of SCLC patients. Signs, symptoms, and associated syndromes of lung cancer are summarized in Table 109-1.

When lung cancer is suspected based on history and physical examination findings, laboratory evaluation and imaging are indicated as summarized in the Diagnostics box. If there is a high degree of suspicion (e.g., an abnormal chest radiograph) a contrast-enhanced computed tomography (CT) scan of the thorax should be performed that includes the liver and the adrenal glands. Imaging should also include evaluation of any sites of suspected metastatic disease. As part of the staging evaluation, most patients will also eventually undergo a positron emission tomography (PET) scan to assess for spread to lymph nodes or distant sites. For patients with neurologic signs or symptoms or seemingly more advanced disease, brain imaging with magnetic resonance imaging (MRI) or CT scan is indicated. In general, the goal of this initial evaluation is to confirm the diagnosis and to establish the stage (i.e., the extent of disease). Staging considerations can be complex, and referral to a thoracic oncology program or a pulmonologist is indicated if the initial evaluation suggests likely lung cancer.

Staging for NSCLC is based on the TNM (tumor, nodes, metastases) system and is described in detail in the American Joint Committee on Cancer (AJCC) cancer staging manual.¹⁰ The tumor stage (T1 to T4) is based on the size, location, and involvement of adjacent structures. The nodal stage (N1 to N3) is divided into three categories: N1 (ipsilateral peribronchial or hilar lymph nodes), N2 (ipsilateral mediastinal nodes), and N3 (contralateral or supraclavicular nodes). Metastatic (M) spread is present or absent. A simplified schema of staging and treatment is presented in Table 109-2. Staging will help identify patients who are candidates for curative therapies (surgery or definitive chemoradiation) as opposed to palliative therapies (chemotherapy and/or radiation therapy). SCLC uses a more simplified staging scheme wherein disease is determined to be either limited stage or extensive stage.

TABLE 109-2

Simplified Schema for Staging and Treatment of Lung Cancer

Stage	Simplified Staging Description	Typical Treatment Strategies
NON–SMALL CELL LUNG CANCER
I	Small tumors without any lymph node involvement	Surgical resection Stereotactic body radiation therapy (SBRT) for nonsurgical candidates
II	Medium sized tumors that may invade adjacent structures (i.e., chest wall or diaphragm) OR Smaller tumors that have also spread to nonmediastinal (e.g., hilar) lymph nodes on the same side	Surgical resection with consideration of adjuvant chemotherapy Definitive chemotherapy or radiation for nonsurgical candidates
IIIA	All but the largest tumors that have also spread to the mediastinal lymph nodes on the same side OR The largest tumors (i.e., those that invade structures such as the heart, great vessels, trachea, vertebral body) but have not yet spread to the mediastinal lymph nodes	An area of ongoing debate May involve preoperative chemotherapy with or without radiation followed by surgery or definitive chemotherapy or radiation therapy
IIIB	Any size tumor that has also spread to the mediastinal lymph nodes on the opposite side or to any supraclavicular lymph nodes OR The largest tumors (as earlier) that have also spread to mediastinal lymph nodes on the same side	Not considered resectable Definitive chemotherapy or radiation therapy
IV	Tumors that have spread to distant sites (e.g., bone, brain, adrenals, or contralateral lung) or that cause malignant pericardial or pleural effusions	Not curable Palliative treatment involving chemotherapy or targeted therapy
SMALL CELL LUNG CANCER
Limited	Disease that can be encompassed within one radiation port and that generally corresponds to one hemithorax with the associated lymph nodes	Chemotherapy and radiation
Extensive	Disease that has spread beyond the hemithorax or to distant sites	Palliative chemotherapy

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