The chest has two lungs (a right lung and a left lung) (Fig. 68-1). Each lung is divided into independent lobes, with separate segments. Each segment (and therefor each lobe) maintains its own individual vascular and lymphatic network such that removal of a segment or a lobe does not disturb the vascular or lymphatic patterns of neighboring lung segments. Furthermore, tumors that arise in one segment usually follow a separate and individual drainage pattern which allows for the curative removal of subunits of each lung without jeopardizing the viability of the whole lung. Thus knowledge of pulmonary architecture is crucial to the management of lung cancer.

The right lung is marginally larger because the left lung accommodates the heart by having only 8 segments compared with the right lung, which has 10 segments. Each lung has at least one fissure that divides the lung into smaller lobes. The left lung is divided in two by a single horizontal fissure that creates an upper and lower lobe. The right lung has two fissures, one horizontal and one oblique. These fissures delineate three lobes: upper, middle, and lower. A normal anatomic variant includes the presence of an azygos lobe (see Fig. 68-1, inset), which is usually found at the apex of the right lung. This small variant lobe is separated from the upper lobe by a deep fissure-like groove that cradles the azygos vein.

The lobes of the left and right lung, in turn, are divided into segments representing areas of lung served by different bronchioles, as shown in Figure 68-2. This figure also shows the intimate relationship between the lungs and tracheobronchial tree. The trachea lies anterior to the esophagus (not shown). At the bifurcation of the trachea, or carina, the left and right mainstem bronchi branch off, and each branch enters the hilus of its respective lung. These, in turn, divide into progressively smaller airways, called bronchioles that form a root-like network that extends through the sponge-like tissues of the lung. The exterior layer of the bronchi is composed of cartilage with rings of smooth muscle that permit the bronchi to expand and retract on inspiration and expiration. The cartilaginous segments become more irregular at the distal end of this network, and there are none on the bronchioles.

Lung cancer was first given status as a global epidemic in the 1950s, when decades of cigarette smoking began to take their toll. It continues to be the leading cause of cancer-related deaths among both men and women worldwide.¹ Based on best available data, the worldwide incidence of lung cancer accounts for 1.2 million new cases and 1.1 million cancer deaths annually.² Estimates for 2012 in the United States alone, project 226,160 new cases of lung cancer and 160,340 lung cancer deaths.¹ It is the most common thoracic malignancy compared with esophageal cancer and mesothelioma that account for approximately 12,000 and 3000 yearly cancer deaths, respectively. More deaths in the United States are due to lung cancer than to breast, prostate, and colorectal cancer combined.¹

The bulk of patients with lung cancer can be divided into two major groups based on treatment and prognosis: small-cell lung cancer (SCLC) and non–small-cell lung cancer (NSCLC). SCLC is the more aggressive form and usually has spread systemically by the time of diagnosis. Untreated, the mean survival is 2 to 4 months. Median survival with treatment is between 18 and 36 months.

Currently, SCLC accounts for 15% to 20% of new lung cancer cases per year in the United States. The malignancy is characterized by a proliferation of small anaplastic cells. Because of its tendency to early metastasis, the cancer usually is not amenable to surgical resection, and hence, surgery plays only a limited role in its management. It is, however, modestly responsive to systemic treatment with chemotherapy.³ The combination of etoposide and cisplatin/carboplatin, with radiotherapy as appropriate, remains the standard of care for both limited stage (LS) and extensive stage (ES) disease.⁴ Recent innovations, including the addition of thoracic radiation to systemic chemotherapy protocols, increasing the intensity of thoracic radiation, and prophylactic cranial irradiation,⁵ have produced some benefits in terms of prolonging disease-free intervals and survival.⁶ Current practice guidelines from the American College of Chest Physicians (ACCP) outline the role of each of these modalities (Table 68-1).⁷ Surgery may be rarely recommended and may have a survival benefit in carefully selected patients with stage I SCLC, after thorough mediastinal evaluation.⁸

In contrast, the role of surgery in NSCLC is more clearly defined. Surgical treatment of early-stage disease provides the best chance for cure. NSCLC is comprised of three major histopathologic subtypes: squamous cell carcinoma, adenocarcinoma, and adenocarcinoma in situ (formerly bronchioloalveolar cancer [BAC]), and large cell carcinoma. The nomenclature for BAC was changed to adenocarcinoma in situ in the seventh edition of the AJCC/UICC manual for TNM staging.⁹ These cancers (NSCLC) constitute approximately 80% of lung malignancies. They tend to spread more slowly than SCLC with a reduced potential for systemic metastases, and hence, there are more opportunities for early intervention. Nevertheless, many patients with NSCLC have advanced disease at presentation. Surgery is the cornerstone for treatment of early-stage NSCLC (stages I and II) and offers the best chance for cure. Stage III or IV lung cancers generally are treated with a variety of nonsurgical multimodality protocols. However, selected patients with stage III, and rarely stage IV disease, may be curatively treated with multimodality therapy and surgery. The opportunity for surgical resection depends on the degree of invasion of local structures and the extent of mediastinal nodal disease.¹⁰ A small proportion of lung cancers (<1%) do not exhibit tumors by radiologic criteria. These cancers, termed occult cancers, are diagnosed by screening bronchoscopy and sputum cytology.

All lung cancers share a common etiology in environmental or direct exposure to tobacco. Cigarette smokers experience a 15- to 50-fold increased risk of developing lung cancer in comparison with lifetime nonsmokers. Smoking cessation among long-term smokers decreases lung cancer risk, with the diminution of risk proportional to years of smoking abstinence. More than 50% of lung cancer cases are currently diagnosed in former smokers. Nevertheless, 15% to 18% of lung cancers arise in individuals who have never smoked, and in this group, lung cancer represents the fifth most deadly cancer worldwide.¹¹ There is a confirmed relationship between adenocarcinoma in situ and mutations of malignant cell surface tyrosine kinase receptors, specifically, the epithelial growth factor (EGFR) receptors and KRAS receptors.¹² These somatic mutations render tumors susceptible to treatment with specific inhibitors by tyrosine kinase cellular pathways.

Despite an encouraging age-adjusted decline in lung cancer mortality rate in the 1990s, the absolute number of lung cancer deaths in the United States has increased dramatically since the 1950s because of a growing population of increasingly elderly persons (age >70 years).¹³ Other characteristics of the lung cancer pool in the United States include a pronounced increase in this cancer in women, now claiming more lives than breast cancer, and a dramatic shift with a decrease in squamous cancers and an increase in adenocarcinomas.

The link between cigarette smoking and lung cancer was demonstrated epidemiologically in more than a dozen case-control studies of the early 1950s,¹⁴ followed by two prospective cohort studies from the United Kingdom.^15,16 The Surgeon General of the United States used these data in combination with established epidemiologic criteria of causality—consistency, strength, specificity, temporal relationship, and coherence of association between the disease and the disease-associated variable—to conclude in the 1964 Surgeon General’s Report that “cigarette smoking is causally related to lung cancer in men.” Because of the indisputable link between lung cancer and cigarette smoking, it is considered one of the most preventable forms of all human cancers. In the United States, 80% of cases can be attributed to smoking (90% men; 79% women). Direct evidence of this cause–effect relationship has been demonstrated using genetic amplification techniques.¹⁷ Specifically, it has been demonstrated that a metabolite of benzo[α]pyrene, a component of cigarette smoke, damages three specific loci on the p53 tumor suppressor gene. These loci have been found to be abnormal in approximately 60% of primary lung cancers.

Lung cancer susceptibility may be amplified by other environmental factors. Asbestos, radon, arsenic, ionizing radiation, haloethers, polycyclic aromatic hydrocarbons, nickel, family history, molecular genetic factors, presence of other benign lung disease (e.g., emphysema, chronic obstructive pulmonary disease, and interstitial lung disease), dietary factors (e.g., antioxidants and fat), and indirect (second-hand) exposure to cigarette smoke all have been implicated.

Early detection of lung cancer may be the best chance for cure, but achieving a consensus about lung cancer screening eluded investigators for many years. The negative results of four lung cancer screening trials implemented in the 1970s had a lasting impact on recommended practice guidelines for the treatment and management of lung cancer. Three of these trials were sponsored by the National Cancer Institute under the aegis of a program called the Cooperative Early Lung Cancer Detection Program: the Mayo Lung Project,¹⁸ the Memorial Sloan Kettering Lung Project,¹⁹ and the Johns Hopkins Lung Project.²⁰ A fourth trial was conducted in eastern Europe: the Czechoslovakia Study on Lung Cancer Screening.²¹ The screening method employed in all these studies consisted of plain-film chest x-ray with sputum sampling for cytology. Unfortunately, none of these randomized studies demonstrated a statistically significant correlation between lung cancer screening and mortality reduction. Consequently, the American Cancer Society, which monitors clinical trials and issues guidelines on early cancer detection, was unable to recommend lung cancer screening as the standard of care.²²

Disappointing results with chest x-ray and sputum cytology prompted the investigation of low-dose helical computed tomography, which appeared to be more promising as a screening tool than conventional x-ray for the detection of small (<2 cm) pulmonary nodules. The Early Lung Cancer Action Project (ELCAP) was initiated by investigators at Weill Cornell Medical College to evaluate this effort.²³ On the basis of average tumor size in a baseline screening of 1000 high-risk asymptomatic individuals, the ELCAP investigators found that 80% of nodules diagnosed were of clinical stage I. These findings were reported in Lancet in 1999.²³

In 2002, the National Lung Screening Trial (NLST), a joint effort of the Lung Screening Study (LSS), and the American College of Radiology Imaging Network (ACRIN) began randomly assigning patients to a 3-year course of annual screening with either low-dose CT or chest radiography. Groundbreaking results showing that a 20% mortality reduction could be achieved with low-dose CT were published in the New England Journal of Medicine and in Radiology in 2011.^24,25

To assess the clinical implications of these findings, the American Association for Thoracic Surgery organized a multispecialty taskforce to create guidelines for the clinical management of patients with high risk of developing lung cancer and for survivors of previous lung cancers.^26,27 The gist of these recommendations is that screening with low-dose CT should be conducted annually in North Americans between 55 and 79 years of age who have a 30 pack-year history of smoking. Long-term cancer survivors should be followed with annual low-dose CT until the age of 79 years. Annual low-dose screening should be offered to individuals starting at age 50 if they have a 20 pack-year history with an additional cumulative risk of 5% or greater over the following 5 years.

Despite the benefits of increased pulmonary nodule detection afforded by low-dose CT, the false-positive rate remains high and better methods of distinguishing benign from malignant nodules are needed to avoid unnecessary surgery and keep the costs of surveillance low. Clinical testing that combines fine-needle aspiration (FNA) biopsy with molecular cytologic testing is one approach currently being investigated to improve the diagnosis of benign versus malignant lesions.²⁸

The International Agency for Research on Cancer (IARC) is a specialized branch of the World Health Organization (WHO) that promotes international collaboration in cancer research. Among other works, the IARC publishes the WHO Classification of Tumors, a series of organ and system-specific pathologic tumor classifications that undergo periodic review and update. Relevant to our field, the WHO provides the framework for the pathological classification of lung cancer. Since inception, that framework has relied principally on the pathologic evaluation of routinely stained biopsy specimens and cytologic preparations. In clinical practice, however, pathologists have increasingly relied on additional tests, such as immunohistochemistry, to distinguish cancer subtypes. Classification of lung carcinomas by histopathologic subtype, for example, provides important information about prognosis, improves the stratification of staging with survival, and aids in the selection of optimal treatments. The latest edition, Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart, was published in 2004 and incorporates a number of important developments including the recognition of lung carcinoma heterogeneity, the introduction of diagnostic immunohistochemical staining (IHC) techniques for lung cancer subtype determination, and the recognition of newly described entities such as fetal adenocarcinoma, cystic mucinous tumors, and large cell neuroendocrine carcinoma.²⁹

In 2011, a multidisciplinary panel of experts from the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) proposed major changes in the way lung adenocarcinoma is diagnosed that alter the pathologic classification of lung cancer in a fundamental way (Table 68-2).³⁰ For the first time, recommendations were established regarding the classification of resection specimens, biopsies, and cytology specimens, as well as diagnostic terms and criteria for other major histologic subtypes in addition to adenocarcinoma.³¹ These changes respond to the increasing understanding of pathology with respect to the extent of cancer invasion and its impact on personalized medicine, as well as the importance of histologic classification and molecular testing in stratifying patients for specific therapies.³² A detailed presentation of these changes is beyond the scope of this chapter. Table 68-3 provides a brief summary of the major differences in the classification of lung adenocarcinoma between the WHO classification of 2004 and the recommendations proposed by the IASLC/ATS/ERS.^33,34 Future pathologic systems of lung cancer may incorporate molecular subtyping as a histo-cyto-molecular classification system.