Cancer of the Lung : Non–Small Cell Lung Cancer and Small Cell Lung Cancer

Risk Factors

The cause of the large majority (80%) of lung cancers is cigarette smoking. There is a massive compilation of scientific evidence from epidemiologic studies conducted around the world since the 1950s demonstrating the link between smoking and lung cancer. Epidemiologic research has also revealed that several other factors have been implicated as causes of lung cancer, although none to the extent of tobacco. Cigarette smokers have been shown to have large increases in the risk of lung cancer. Deep sequencing studies have estimated that smoking a pack of cigarettes a day for a year may cause normal lung cells to accumulate on average 150 mutations. Numerous investigations typically show 10-fold or greater increases in risk of this cancer among smokers compared with those who have never smoked. One of the largest studies is the American Cancer Society's prospective cohort study of over 1 million Americans, in which an over 20-fold excess of lung cancer has been observed among men who were current smokers at the start of the follow-up in the early 1980s. In contrast, even the most prolonged and intense exposures to asbestos, perhaps the most prominent occupational cause of lung cancer, are associated with no more than about fivefold increases in risk of lung cancer.

Risks of lung cancer are lower in persons who quit smoking than in those who continue smoking. The reductions in risk indicate that quitting smoking is beneficial (and conversely that continuing to smoke is harmful). Risk among former smokers on average is less than one-half that of those who continue to smoke. In the aforementioned American Cancer Society cohort study, former smokers had a ninefold increase in lung cancer compared with men who had never smoked versus the 20-fold excess in those who continued to smoke. Such relative reductions have been consistently seen, with the size of the reduction in risk increasing the longer the person has continued to not smoke, although in general, even long-term former smokers have higher risks of lung cancer than those who never smoked.

Cigarette smoking has been shown to increase risk of all the major lung cancer cell types. The magnitude of the increase varies by histologic type, however, with highest risks for squamous cell, small cell, and large cell carcinomas of the lung. Some early studies tended to show only small increases in risk of adenocarcinoma among smokers, but more recent studies have indicated that the excess of lung adenocarcinoma is substantial.

Cigarette smoke has also been implicated in increasing risk of lung cancer among nonsmokers. A 2006 update of the Surgeon General's report declared that there is sufficient evidence to list passive smoking as an established cause of lung cancer and called for further control of environmental tobacco smoke (ETS) exposures. The risk from ETS is far less than from active smoking, with about a 20% to 30% increase in lung cancer observed among nonsmokers married for many years to smokers, in comparison with the 2000% increase among continuing active smokers. Nevertheless, cancer control activities based on the knowledge that ETS exposure may convey an increased risk of lung cancer have helped reduce exposures in public places and have also provided additional incentive for smokers to quit the habit.

Although cigarette smoking is the dominant cause of lung cancer, several other risk factors for this cancer have been identified. These include occupational exposures to asbestos and some other workplace agents, some of which have been evaluated for nearly as long as cigarette smoking. Among the occupational agents considered to be known lung carcinogens are arsenic, bischloromethyl ether, hexavalent chromium, mustard gas, nickel (as in certain nickel refining processes), and polycyclic aromatic hydrocarbons. Several other occupational exposures have been associated with increased rates of lung cancer, but the causal nature of the association is not clear. Epidemiologic studies have attempted to assess the potentially synergistic interrelationship between certain workplace exposures and smoking. Risk of lung cancer in men exposed to asbestos who also smoked was originally thought to be exceptionally high (with early reports of 50-fold or greater excesses compared with unexposed nonsmokers), but modeling of larger data pools has suggested that asbestos and tobacco combine to enhance lung cancer risk in a less than multiplicative manner. Occupational observations have also provided clues to the mechanisms of lung cancer induction. Risk of lung cancer among asbestos-exposed workers, for example, is increased primarily in those with underlying asbestosis, raising the possibility that the scarring and inflammation produced by this fibrotic nonmalignant lung disease may in many cases (though likely not in all) be the trigger for asbestos-induced lung cancer.

Increased risks of lung cancer have also been associated with other factors. Diet and nutrition are thought to be involved, because numerous investigations have shown somewhat higher risks of this cancer among those with low fruit and vegetable intake during adulthood. The early observational studies led to hypotheses that specific nutrients, in particular retinoids and carotenoids, might have chemopreventive effects for lung cancer. Randomized clinical trials were launched but failed to validate this hypothesis when reports from interventions involving supplementation with β-carotene in trials both in Finland and in the United States found increased rather than decreased incidence of lung cancer among the supplemented. The current consensus regarding diet and lung cancer remains muddled, with a minor role for nutritional factors likely, but difficult to assess epidemiologically. Ionizing radiation has been established as a lung carcinogen, most convincingly demonstrated from studies showing modestly increased rates of this cancer among persons exposed to the atomic bombs of Hiroshima and Nagasaki and large excesses among workers exposed to alpha irradiation from radon in underground uranium mining. Extrapolations from the high exposures in mines to low-level radon exposures in homes, and direct observations from case-control studies assessing measured levels in homes, have suggested that prolonged radon exposures above the recommended remedial levels might impart a risk of lung cancer equal to or greater than that of ETS. Prior lung diseases such as asbestosis (mentioned earlier), chronic bronchitis, emphysema, and tuberculosis also have been linked to increased risks of lung cancer. Although smoking itself is a cause of chronic obstructive pulmonary disease (COPD), the link between chronic bronchitis and emphysema and lung cancer persists after adjustment for smoking, with up to about a doubled smoking-adjusted cancer risk among those with COPD.

Familial clustering of lung cancer has been observed, raising the possibility of inherited traits that may increase risk among some individuals, with risk about doubled in families with prior lung cancer. Individuals with inherited mutations in retinoblastoma (RB) and p53 (Li-Fraumeni syndrome) genes may develop lung cancer. Genome-wide association studies (GWASs) have identified four genetic loci for lung cancer risk including two on 5p15 (TERT-CLPM1L), 15q25.1 (CHRNA5-CHRNA-3 nicotinic acetylcholine receptor subunits) and 6p21 (BAT3-MSH5). A rare germline mutation involving the epidermal growth factor receptor (EGFR) within exon 20 that results in an amino acid substitution at position 790 from threonine to methionine (T790M) has been linked to lung cancer susceptibility in never-smokers. Smoking also clusters within families, so some of the familial aggregation of lung cancer may be smoking related. Nevertheless, there appear to be multiple genetic factors that help determine the way in which individuals metabolize, detoxify, repair, or otherwise respond to lung carcinogens, including the carcinogens in cigarette smoke, as discussed in more detail later in this chapter.

Tissue and Cytologic Diagnosis of Lung Cancer

The diagnosis of lung cancer can be made based on tissue specimens such as endobronchial and transbronchial biopsy specimens or resected specimens, or by assessment of cytologic specimens from procedures such as transbronchial or transthoracic fine-needle aspiration (FNA), bronchial brushings and washings, or bronchoalveolar lavage or by evaluation of sputum or pleural fluid. The diagnostic yield depends on several factors including location (accessibility) of the tumor, tumor size, tumor type, and technical aspects of the diagnostic procedure including the experience level of the bronchoscopist and pathologist. In general, central lesions such as squamous cell carcinomas and SCLC, or endobronchial lesions such as carcinoid tumors, are more readily diagnosed with bronchoscopic examination whereas peripheral lesions such as adenocarcinomas and large cell carcinomas are more amenable to transthoracic FNA or biopsy. Diagnostic accuracy for most specimens in distinguishing SCLC and NSCLC is excellent, with less accuracy for subtypes of NSCLC if immunohistochemical staining is not used.

Bronchoscopic specimens are obtained through bronchial brushings, washings, bronchoalveolar lavage, and transbronchial FNA. Of these, transbronchial FNA consistently demonstrates the highest sensitivity, surpassed only by the use of a combination of bronchoscopic specimens. Overall sensitivity for combined use of bronchoscopic methods is approximately 80%, and if performed together with tissue biopsy, the yield increases to 85% to 90%. In fact, transbronchial FNA is more often diagnostic than transbronchial biopsy when the lesion of interest is submucosal.

Like transbronchial FNA specimens, transthoracic FNA specimens are also diagnostically useful, yielding diagnostic material in 70% to 95% of cases. Sensitivity is highest for larger lesions and peripheral tumors. In general, specimens obtained with FNA, whether transbronchial, transthoracic, or endoscopic ultrasound guided, are superior to other specimen types. The superiority of FNA specimens is primarily due to the higher yield of lesional tumor cells with fewer confounding factors such as obscuring inflammation and reactive nonneoplastic cells.

Cytologic assessment of sputum is inexpensive and noninvasive but has a lower yield than other specimen types owing to poor preservation of the cells and more variability in acquiring a good-quality specimen. The yield for sputum cytology is highest for larger and centrally located tumors such as squamous cell carcinoma and SCLC, although occasionally an accurate diagnosis is possible with tumors located more peripherally within the lung. The specificity for sputum cytologic assessment averages close to 100%, although sensitivity is generally less than 70%. The accuracy of sputum cytology improves with increased numbers of specimens analyzed, and consequently analysis of at least three sputum specimens is recommended. Sputum cytologic evaluation has also been extensively studied with varying success as a screening tool for early detection of lung cancers. Sputum cytologic analysis is not currently recommended as a routine screening tool, but advances in molecular diagnostic techniques may result in a resurgence in its use.

Squamous Cell Carcinoma

Squamous cell carcinoma ( Fig. 69.3 ) is typically a centrally located tumor affecting large airways. It is strongly associated with tobacco smoking. The current WHO classification recognizes two major subtypes: keratinizing and nonkeratinizing squamous cell carcinoma. Keratinizing squamous cell carcinomas show varying light microscopic evidence of keratinization (in the form of keratin pearls, individual cell keratinization, and/or intercellular bridges). Nonkeratinizing squamous cell carcinomas are poorly differentiated tumors lacking easily recognizable features of keratinization and require immunohistochemical confirmation of their squamous nature. The most common pattern is one of infiltrating nests of malignant squamous cells ( Fig. 69.3A ) with central necrosis, often resulting in cavitation. The tumor commonly affects central airways ( Fig. 69.3B ), displaying exophytic and endobronchial growth. A basaloid variant ( Fig. 69.3C ) can mimic other basaloid or neuroendocrine tumors histologically. In evaluating cytologic specimens containing squamous cell carcinoma, intercellular bridges are not usually identified, but keratin can be clearly seen when present. In addition, the tumor tends to consist of sheets of cells rather than the three-dimensional groups of cells characteristic of adenocarcinomas ( Fig. 69.3D ).

Squamous cell carcinomas of the lung are morphologically identical to extrapulmonary squamous cell carcinomas, and IHC cannot be used to distinguish primary from metastatic tumors. Separating a primary from metastatic squamous cell carcinoma requires clinical correlation. In rare cases in which the invasive tumor is clearly associated with squamous dysplasia or a squamous cell carcinoma in situ (CIS) component, a primary tumor is highly likely. The differential diagnosis of squamous cell carcinoma of the lung includes reactive processes that may result in squamous metaplasia with reactive atypia such as that observed with infection or radiation-induced injury. In these cases, clinical correlation is also essential. Poorly differentiated squamous cell carcinomas, such as basaloid squamous cell carcinoma, commonly elicits the differential diagnosis of SCLC, and use of immunohistochemical stains including neuroendocrine markers is required to separate these tumors.

Adenocarcinoma

In North America and Japan, adenocarcinoma is the most common histologic type of lung cancer. As in other lung carcinomas, adenocarcinomas occur predominantly in smokers, although nonsmokers are more likely to develop adenocarcinoma compared with other lung cancer types. Adenocarcinomas tend to occur in the periphery of the lung but can occur centrally, can be multifocal, or can fill an entire lobe. Radiographically, they are associated with solid opacities, ground-glass opacities (GGOs), or mixed patterns, generally correlating with the amount of in situ and invasive components of the tumor. The histologic diagnosis is made based on the light microscopic features of glandular differentiation, which include the presence of glands (acini), papillary and/or micropapillary structures, lepidic (bronchioloalveolar) growth pattern, and in poorly differentiated tumors with a solid pattern of growth, the presence of intracellular mucin ( Fig. 69.4A–E ). Eighty percent of adenocarcinomas demonstrate a mixture of at least two of these patterns, and many mixed adenocarcinomas (>20%) show a focal lepidic pattern. Of these patterns, the solid and micropapillary patterns in adenocarcinomas are associated with a worse prognosis. On cytologic preparations, three-dimensional groups or glandular and papillary patterns may be identified and are diagnostic of adenocarcinoma ( Fig. 69.4F ). Variants of adenocarcinoma include colloid, enteric, and fetal adenocarcinomas.

The 2004 WHO classification introduced the concept of atypical adenomatous hyperplasia (AAH) as a precursor of some adenocarcinomas. Bronchioloalveolar carcinoma (BAC) was defined as a noninvasive tumor, if the strict criteria were followed. This definition arose out of studies showing that noninvasive tumors smaller than 3 cm resulted in a 100% 5-year patient survival ; in addition, tumors with limited fibrosis, smaller size, and limited invasion had a better prognosis. Minimally invasive tumors, although not defined as BAC in the strictest sense, also carried an excellent prognosis. The IASCL/ATS/ERS classification discourages the use of the term bronchioloalveolar carcinoma and advocates use of the diagnosis adenocarcinoma in situ (AIS) for nonmucinous and rarely mucinous lesions 3 cm or smaller with purely lepidic growth (tumor cells lining alveolar walls). The term minimally invasive adenocarcinoma (MIA) is to be applied to nonmucinous and rarely mucinous lesions 3 cm or smaller with invasion limited to 5 mm or less. Lepidic predominant adenocarcinoma is a diagnosis proposed for nonmucinous lesions with foci of invasion greater than 5 mm. Most tumors previously called mucinous BAC are felt to actually represent invasive tumors and are thus reclassified as invasive mucinous adenocarcinoma in the IASLC/ATS/ERS criteria. Of note, the diagnosis of AIS or MIA cannot be rendered on small biopsy or cytologic specimens, because the entire tumor has to be examined to exclude or measure invasion.

AAH is a small preinvasive lesion (usually <5 mm) consisting of mild to moderately atypical cells lining the alveoli. AAH is an incidental lesion usually found in lung tumor resection specimens. Because these lesions (along with AIS) preserve the underlying lung architecture and alveolar spaces, they may appear as GGOs radiographically. Although when associated with malignancy it is most often associated with adenocarcinoma of the lung, AAH has also been identified in conjunction with other lung carcinomas and metastasis.

The IASLC/ATS/ERS classification recommends use of com­prehensive histologic subtyping of adenocarcinomas to make a semiquantitative assessment of the percentages of the various histologic patterns of adenocarcinoma: acinar, papillary, micropapillary, lepidic, and solid. At the time of pathologic diagnosis, tumors should be classified according to the predominant histologic subtype. If additional subtypes are present, they also should be listed. Studies using this classification have demonstrated prognostic significance in stage I cancers based on the predominant pattern. AIS and MIA resulted in 100% disease-free survival (DFS) at 5 years. Lepidic, acinar, and papillary predominant tumors had intermediate prognosis. Solid, micropapillary, and colloid predominant and invasive mucinous and mixed mucinous and nonmucinous adenocarcinomas had the worst prognosis.

The differential diagnosis of adenocarcinoma is broad and includes not only metastatic adenocarcinomas from other sites, but also tumors such as mesothelioma, which can show histologic similarities to adenocarcinoma. Clinical data including location of the tumor or tumors and history of prior malignancy are the most helpful feature in differentiating primary from metastatic tumor, but immunohistochemical stains may help further narrow the differential diagnosis when a metastatic lesion is suspected (see later discussion of IHC).

Other Non–Small Cell Carcinomas

Less common aggressive NSCLC subtypes include large cell carcinoma, pleomorphic carcinoma, spindle cell carcinoma, and giant cell carcinoma, each representing single-digit percentages of the lung carcinoma pie. Carcinosarcoma, pulmonary blastoma, lymphoepithelioma-like carcinoma, and NUT carcinoma are even rarer. Large cell carcinoma is defined as an undifferentiated NSCLC without light microscopic and immunohistochemical evidence of squamous or glandular differentiation after examination of the entire tumor at resection ( Fig. 69.5 ). Histologically, large cell carcinoma shows sheets of large malignant epithelioid cells with abundant cytoplasm and vesicular nuclei with prominent nucleoli. There are frequent mitoses and tumor necrosis. In the search for glandular or squamous differentiation, the diagnosis of large cell carcinoma requires examination of the entire tumor mass, so it cannot be rendered on small biopsy specimens or cytologic preparations. Some tumors histologically classified as large cell carcinoma may show evidence of glandular, squamous, or neuroendocrine differentiation with electron microscopy. Furthermore, because IHC is now routinely used to highlight areas of glandular and squamous differentiation (see later discussion of IHC), more tumors are classified as either squamous cell carcinoma or adenocarcinoma and thus the diagnosis of large cell carcinoma is becoming less common. Pleomorphic carcinoma is a poorly differentiated NSCLC that shows at least 10% of spindle cell and/or giant cell carcinoma components in combination with adenocarcinoma or squamous cell carcinoma or undifferentiated NSCLC components ( Fig. 69.6 ). Spindle cell carcinomas and giant cell carcinomas are composed of only respective single cell–type components. The tumors carry a poor prognosis even in early-stage disease. Because of the aggressive nature, distant metastasis, including to unusual sites, are common at presentation. Approximately 40% to 60% of the tumors show expression of the site-specific markers, which can be helpful in separating these tumors from metastasis.

Neuroendocrine Tumors of the Lung

Neuroendocrine tumors of the lung include a spectrum of lesions from the indolent to the most aggressive pulmonary neoplasms. The four main neuroendocrine tumors of the lung are typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and SCLC ( Fig. 69.7 ). The main distinguishing histopathologic features of these tumors include the presence of neuroendocrine morphologic features (peripheral nuclear palisading, nuclear rosettes, and trabeculation) in combination with immunohistochemical evidence of neuroendocrine differentiation (expression of neuroendocrine markers). In general, it is helpful to think of these tumors according to their clinical characteristics. Carcinoid tumors tend to occur in younger nonsmokers and are less aggressive, whereas SCLC and LCNEC occur in smokers and behave aggressively. Separation of these tumors relies on cytologic features and histologic evaluation of proliferative activity (mitotic count and presence or absence of necrosis). The WHO classification emphasizes mitotic count in defining and separating these tumors ( Table 69.3 ). Although the use of IHC for Ki-67 (MIB1)—a cell proliferation marker—is not formally recognized in the WHO classification, its usefulness in separating carcinoid tumors from SCLC and LCNEC has been documented in limited biopsy material. The rate of Ki-67 staining is usually less than 2% for TC, less than 20% (and usually approximately 10%) for AC, and greater than 25% (commonly greater than 50%) for SCLC and LCNEC. In addition to assessment for the distinct histologic appearance, IHC may also be performed to verify the neuroendocrine nature of a tumor and thus differentiate neuroendocrine tumors from other NSCLC subtypes.

Small Cell Carcinoma

SCLC is a poorly differentiated neuroendocrine tumor that tends to occur centrally and has strong association with cigarette smoking. Incidence rates of SCLC are higher in men than in women, but a higher percentage of lung cancers are of SCLC type in women than in men. SCLC consists of cytologically malignant epithelioid cells with scant cytoplasm, nuclei with granular (“salt and pepper”) chromatin without prominent nucleoli, and more than 10 mitoses per 2 mm ² (usually more than 50 mitoses per 2 mm ² ). The tumor cells are arranged in sheets, but also present are the rosettes, trabeculae, or peripheral palisading of cells along the edges of nests. In small biopsy specimens, crush artifact with smearing of nuclear material and nuclear “molding” is commonly observed. The tumor cells display scant cytoplasm and thus appear small—up to two to three times the size of a resting lymphocyte; however, variation in size can be seen, and it is the nuclear features that allow diagnosis, not strictly cell size. The characteristic features are usually easily identified in well-preserved cytologic specimens but may be more difficult to differentiate from other poorly differentiated tumors at liquid-based cytologic assessment or with less well-preserved specimens or small biopsy specimens ( Fig. 69.8 ). As with other histologic types of lung carcinoma, SCLC may occur in combination with NSCLC components. Combined SCLC and LCNEC, combined SCLC and adenocarcinoma, and combined SCLC and squamous cell carcinoma have all been well documented. The differential diagnosis of SCLC includes poorly differentiated NSCLC, especially poorly differentiated squamous cell carcinoma, and neuroendocrine carcinomas, in addition to nonepithelial malignancies such as lymphoma, and some rare sarcomas (e.g., synovial sarcoma).

Immunohistochemistry of Lung Tumors

With the advent of different therapies for adenocarcinoma and squamous cell carcinoma, it has become important to separate the two on small biopsy and cytologic specimens. When the light microscopic features characteristic of these tumors are lacking, their further subclassification relies on immunohistochemical studies. Expression of TTF-1 (thyroid transcription factor 1, a protein that regulates transcription of genes specific for the thyroid, lung, and diencephalon) and/or napsin A (a member of the aspartic protease family, expressed in normal lung and kidney) ( Fig. 69.9 ) in poorly differentiated NSCLC favors a diagnosis of adenocarcinoma. Expression of high-molecular-weight cytokeratins, such as CK5/6, and/or p63 (a member of the p53 family of transcription factors), and/or p40 (more specific isoform of p63) in poorly differentiated NSCLC favors a diagnosis of squamous cell carcinoma. A percentage of poorly differentiated NSCLC may not show clear separation at immunohistochemical evaluation and will still fall into the category of NSCLC, not otherwise specified.

IHC may also be used to confirm neuroendocrine differentiation within a tumor. Neuroendocrine markers include CD56 or neural cell adhesion molecule (NCAM), synaptophysin, and chromogranin A. Neuron specific enolase (NSE) shows significant nonspecific staining of nonneuroendocrine tumors and should not be used. Most often a combination of these stains (e.g., CD56, synaptophysin, and chromogranin A) is used to establish a diagnosis. These markers support neuroendocrine differentiation, but do not distinguish between specific types of neuroendocrine tumors.

IHC is also helpful in distinguishing primary lung tumors from malignancies metastatic to the lung. This is especially true for separating primary lung from metastatic adenocarcinomas. TTF-1 is expressed in over 70% of pulmonary adenocarcinomas. When positive, TTF-1 is a reliable indicator of a lung primary, provided a thyroid origin has been excluded. A negative TTF-1 finding, however, does not exclude the possibility of a lung primary. Important to note, TTF-1 has been recognized to lose its site specificity in high-grade neuroendocrine tumors because its expression has been documented in SCLC of extrapulmonary origin. Cytokeratins 7 and 20 used in combination also assist in categorizing certain tumors. These stains are not specific for a particular site of origin but can narrow the differential diagnosis based on their pattern of expression.

Because there is significant morphologic overlap between lung carcinomas and mesothelioma, IHC is required in diagnosis of these tumors. Immunohistochemical markers for CK5/6, calretinin, and Wilms tumor gene 1 (WT1) are among most useful in supporting the diagnosis of mesothelioma; however, because none of these display 100% sensitivity, they are supplemented by so-called adenocarcinoma markers such as BerEP4, MOC31, and carcinoma embryonic antigen (CEA) and used as a panel. For a reliable diagnosis of mesothelioma, it is recommended that expression of at least two “mesothelial” markers be shown.

A summary of commonly used immunohistochemical stains is shown in Table 69.4 .

High-Risk Population: A Susceptible Subgroup

As noted, a challenging problem in screening for lung cancer is the definition of a “high-risk” population—the population that could best benefit from lung cancer screening. Individuals “at risk” include current and former smokers, those with specific various occupational exposures (e.g., asbestos; see section on epidemiology), the presence of airflow obstruction, a family history of lung cancer, older individuals, and those with a prior history of a cancer of the aerodigestive tract. Individuals who smoke expose their entire aerodigestive tract to multiple carcinogens, and therefore it is not surprising that this population experiences a high rate of second primary tumors, estimated at 1% to 4% per patient per year. However, mere recognition of these features is not sufficient to identify high-risk individuals. For example, although smoking is an obvious risk factor for lung cancer—the cumulative risk of dying from lung cancer for a lifelong smoker is estimated to be approximately 16% in men and approximately 10% in women —the risk of developing lung cancer varies greatly among individual current and former smokers. For example, in the Carotene and Retinol Efficacy Trial (CARET), a large, randomized trial of lung cancer prevention, the 10-year cancer risk among current and former smokers ranged from less than 1% to 15%. An example of an individual with a relatively low risk of developing lung cancer would be a 51-year-old woman who smoked one pack per day for 28 years and quit 9 years ago. By contrast, a 68-year-old man who smoked two packs per day for 50 years and continued to smoke might have a 15% risk of lung cancer. Both of these individuals would be potentially eligible for screening, and yet the payoff could be quite different. This suggests that an accurate risk prediction model may greatly facilitate the admission of subjects in screening (or chemoprevention) trials. Many attempts to improve these prediction models have been made—for example, with use of demographic and clinical and now molecular biomarkers such as DNA SEX6L polymorphism or DNA sputum cytometric analysis or imaging biomarkers such as the presence of a nodule or emphysema at baseline.

Relative to smokers with normal lung function, smokers with COPD have a fourfold to sixfold elevated risk of lung cancer, making COPD the greatest clinical risk factor in ever-smokers. Low-dose chest computed tomography (LDCT) screens provide an in vivo assessment of both biologically relevant features of indeterminate nodules and the extent of injury reflected by emphysema. The integration of biologic and imaging-based biomarkers to individualize lung cancer risk not only enables identification of individuals most likely to benefit from screening, and perhaps more intensive screening, but also could be used to identify individual smokers at great risk of developing cancer and further convince them to stop smoking, which is the first and most effective step in the prevention of lung cancer and all other smoking-related diseases.

The presence of cytologic atypia in sputum samples reflects the abnormalities that develop in the bronchial epithelium. Moreover, the presence of cytologic atypia has been shown to predict lung cancer risk. The presence of moderate dysplasia or worse cytologic atypia was associated with an increased risk of developing lung cancer in a cohort of heavy smokers with airflow obstruction (adjusted hazard ratio [HR] of 2.8). This translates into a cumulative lung cancer incidence of 10% at 3 years and 20% at 6 years. Given the limitations of cytologic evaluation of sputum samples, however, the study of molecular abnormalities in the sputum (e.g., methylation patterns of specific genes involved in lung cancer progression and cytogenetic alterations) may strengthen the assessment of risk for lung cancer in this population.

Molecular epidemiology may be used to identify patients at risk for developing lung cancer through the identification of specific genes, single-nucleotide polymorphisms, or other genetic traits associated with increased susceptibility to lung cancer. Although many genotypes show increased risk (relatively low odds ratios [ORs]) with lung cancer (e.g., CYP2A6, thymidylate synthase, GSTM1, XPA), their large number and low penetrance make targeted interventions extremely challenging. Assessing genetic susceptibility to lung cancer may allow the identification of susceptible subgroups most likely to represent ideal candidates for early detection. With the exception of the rare EGFR T790M polymorphism, autosomal dominant genes have not been found in association with family history of lung cancer; there is epidemiologic evidence demonstrating a 2.5-times increased risk in any patient with a family history of lung cancer (two affected first-degree relatives) after smoking was controlled for. A region on chromosome 6q23–25 has been identified as a locus of susceptibility with a maximum heterogeneity logarithm of the odds (LOD) score of 2.79, 3.47, and 4.26 for families with three, four, or five or more affected individuals. Further complicating the picture is the role of the environment in modifying these specific genes, the interaction among genes, and evidence to support a genetic predisposition to smoking addiction. If markers of these genetic predispositions can be firmly established, intensive intervention to alter risk factors in these selected populations may alter the clinical outcome.

Imaging Approach

The last decade has witnessed a dramatic improvement in technology allowing for faster, higher-resolution imaging of the chest with reduced radiation exposure. The CT scanner first became available in the 1970s but was impractical for screening owing to its slow speed and high radiation dose. In the mid-1990s, low-dose scanners capable of imaging the chest in less than 15 seconds with radiation doses equivalent to 10 radiographs became available, opening the door to their potential use for screening. Moreover, new bronchoscopic methods also demonstrate promise for the detection of preinvasive lesions. Other imaging modalities such as positron emission tomography (PET) are able to provide metabolic information on lesions and can be combined with CT scan to give detailed resolution.

Biofluid-Based Biomarkers for Lung Cancer

The underlying premise of biofluid-based biomarker research is that molecular alterations of tumor cells lead to the synthesis and shedding of distinct molecular species that can be detected in biofluids. Biofluid-based detection strategies are an attractive approach for screening, because of their ease of acquisition. Biofluids, including peripheral blood and its components (circulating cells, plasma, and serum), exhaled breath condensate (EBC), urine, and sputum, offer noninvasive access to large quantities of samples for analysis. These alterations can lead to the generation of disease-specific molecular species such as altered or methylated DNA, overexpressed mRNA, microRNA, or proteins that can potentially be released into the extracellular microenvironment at a rate that is dependent on multiple variables but mainly tumor growth and shedding rates. Therefore molecular analyses of early-stage lung cancer–related biofluids represent an attractive choice for the discovery and validation of diagnostic biomarkers. The success of this approach will also depend not only on our ability to improve the specificity of our candidate biomarkers but also on the sensitivity of our detection assays. Although various serum biomarkers have been investigated in lung cancer, none has proved useful in general clinical practice, mainly because of the lack of sufficient sensitivity and specificity (reviewed by Barrera and colleagues ). For example, cytokeratin fragment antigen 21.1 (Cyfra-21.1), a marker of cytokeratin, CEA, and tissue polypeptide antigen (TPA) were found to have relatively poor sensitivity (31%–64%) when specificity limits of 95% were set. In addition, most markers reach better sensitivity in advanced disease stages as compared with stage I lung cancer. Therefore their use for early diagnosis or screening has not had an impact on patient care in the clinic. Blood-derived biomarkers used in combination with other clinical, imaging, or molecular tools might play an important role in early detection, in monitoring response to therapy, in risk assessment of recurrence, and in prognosis, especially in intermediate-risk nodules in low-risk individuals or that are PET negative.

In conclusion, LDCT in individuals at high risk now offers excellent sensitivity for detection of lung cancer at an early stage, brings a stage shift among tumors diagnosed, and saves lives. The high sensitivity of these screening tests, however, is associated with a low specificity. Better selection of individuals at highest risk of lung cancer through use of biomarkers of disease and genetic susceptibility may improve their positive predictive values, minimize the false-positive rates and associated unnecessary investigations or treatment, and reduce the cost of the early detection process.

Presenting Signs and Symptoms

Symptoms, signs, and laboratory test abnormalities relating to lung cancer can be classified as those caused directly by the primary lesion, those related to intrathoracic spread or to distant metastasis, and those related to paraneoplastic syndromes. The prototypical lung cancer patient is a current or former smoker of either sex, usually in the seventh decade of life, with symptoms attributable to bulky intrathoracic disease (i.e., cough, dyspnea, chest pain, hoarseness, and/or hemoptysis) or distant metastases (e.g., bone pain, central nervous system [CNS] symptoms). Constitutional symptoms may include weakness, anorexia, weight loss, and, rarely, fever. Apart from the brevity of symptom duration, these parameters fail to clearly distinguish SCLC from NSCLC or even from neoplasms metastatic to the lungs. Lung cancer arising in a lifelong never-smoker is more common in women and certain ethnic groups and tends to be an adenocarcinoma. Such patients also tend to be slightly younger than their smoking counterparts at the time of diagnosis. However, the clinical presentation of lung cancer in never-smokers tends to mirror that of current and former smokers even though lung cancers arising in never-smokers appear to be biologically distinct as evidenced by the differing molecular abnormalities found in tumors derived from smokers and nonsmokers. The prognosis of lung cancer in never-smokers is generally improved compared with cancers in current or former smokers, irrespective of stage. This may be due to the better overall condition of these patients, the higher frequency of actionable genetic abnormalities in tumors from these patients (to be discussed later), or other as yet unknown reasons.

Cough, dyspnea, and chest discomfort are the most common presenting symptoms in lung cancer ( Table 69.7 ). A history of chronic cough with or without hemoptysis in a current or former smoker with COPD aged 40 years or older should prompt a thorough investigation for lung cancer even in the face of a normal chest radiograph. A persistent “pneumonia” without constitutional symptoms and unresponsive to repeated courses of antibiotics also should prompt an evaluation for an underlying cause (e.g., an occult endobronchial lesion), especially if the patient is a current or former smoker. Less frequently, patients present with hemoptysis, which rarely is massive and is usually described as streaks of fresh or old blood in sputum. The spread of disease within the chest may result in hoarseness secondary to a left recurrent laryngeal nerve paralysis and, less frequently, phrenic nerve paralysis. The latter is associated with an elevated hemidiaphragm on standard chest radiographs. Chest wall involvement is commonly accompanied by pain that in turn may serve as a more accurate indicator of chest wall invasion than radiographic studies. Chest wall pain is usually related to direct invasion of the pleura or chest wall by the primary tumor or is due to a rib metastasis. Tenderness may be elicited at the site of rib involvement and, rarely, a soft-tissue mass can be palpated. The chest pain may have a pleuritic component if there is pleural involvement. The disappearance of pleuritic chest pain may signify the development of a pleural effusion that in turn may cause shortness of breath or may worsen existing dyspnea. Venous distention of the neck and chest wall, cyanosis, facial plethora, and upper extremity edema may indicate obstruction of the superior vena cava, which today is most commonly seen with SCLC. Although the heart and other mediastinal structures are often involved with tumor at postmortem examination, only rarely does this involvement serve as the source of a presenting symptom.

Approximately one-third of patients have symptoms as a result of distant metastases. The most common sites of distant metastasis from lung cancer are the bones; liver, adrenal glands, and intraabdominal lymph nodes; brain and spinal cord; and lymph nodes and skin. Lung cancer can metastasize to virtually any bone, with pain being the primary presenting symptom in up to 25% of patients. Similarly, liver metastases are common at initial presentation in both SCLC and NSCLC. However, liver function test results are seldom abnormal until the metastases are numerous and large. Hepatic metastases most commonly produce symptoms of weakness and weight loss. Adrenal lesions (only rarely associated with adrenal insufficiency) and paraaortic lymph node metastases are most commonly seen with SCLC. Intracranial metastases at presentation are most common in SCLC and adenocarcinomas of the lung. Presenting symptoms may include headache, nausea and vomiting, focal neurologic symptoms or signs, seizures, confusion, and personality changes.

The stigmata of COPD in smokers may be the only findings on physical examination, or one may detect lymphadenopathy, hepatomegaly, bone tenderness, or abnormal neurologic findings. Digital clubbing and hypertrophic pulmonary osteoarthropathy (HPO) may be associated with any histologic subtype of lung cancer but are most frequently associated with squamous cell and adenocarcinoma and are least likely to occur in a patient with SCLC. Digital clubbing is more common than HPO, and the latter is characterized by painful symmetric arthropathy and periosteal new bone formation of the distal limbs. Its mechanism of development is unknown. In a published series of 111 consecutive lung cancer patients, clubbing was noted in 29%, with an incidence of 35% in NSCLC and only 4% in SCLC. Up to 20% of patients develop palpable lymphadenopathy in the supraclavicular fossa during the course of the disease. Subcutaneous metastases, although rare, portend a poor prognosis but serve as a readily accessible source of diagnostic material.

Paraneoplastic Disorders

Although many of the symptoms of NSCLC and SCLC are attributable to mass effect and direct impingement on vital organs, less commonly patients with lung cancer have symptoms related to hypercalcemia, hyponatremia, Cushing syndrome, Lambert Eaton syndrome, and other neurologic disorders. These so-called paraneoplastic phenomena can be seen in any histologic type of lung cancer, but are most frequently associated with SCLC. In general, a majority of these paraneoplastic phenomena fall into endocrine or neurologic categories.

Assessment of Intrathoracic Disease

Accurate clinical staging of lung cancer is extremely important because treatment options and prognosis are dictated by stage at presentation. The most significant dividing line is between patients who are candidates for treatment with curative intent (surgery or definitive chemoradiation) and those who are not suitable for such interventions but who will benefit from chemotherapy, radiation therapy (RT), or both. Staging with regard to a patient's potential for surgical resection is most applicable to NSCLC. The basis for staging NSCLC is the TNM system, which was updated in the eighth edition of the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC)/IASLC staging system ( Tables 69.8A and 69.8B ), in effect as of January 2018. For SCLC, a more simplified staging classification is often used (described later). From a practical standpoint, metastases to the hilar or mediastinal lymph nodes are reflected in the N designator. An international lymph node map has been developed as part of the staging process. Determination of metastases to mediastinal lymph nodes constitutes a critical point in staging and treatment recommendations. Patients with mediastinal node metastases may also be selected for multidisciplinary therapy including induction therapy (either chemotherapy or chemoradiotherapy) followed by resection.

Several noninvasive imaging techniques are available to aid in identifying the extent of disease both within and outside of the chest. Some lung cancers are detected with plain chest radiography ( Fig. 69.11 ). However, the chest radiograph is not sufficiently sensitive to accurately assess the mediastinum. Accordingly, a chest CT scan should be performed in all patients with known or suspected NSCLC. The chest CT scan provides anatomic detail that better identifies the location of the tumor, its proximity to local structures, and whether or not lymph nodes in the mediastinum are enlarged (see Fig. 69.11 ). Unfortunately, the accuracy of chest CT scanning in differentiating benign from malignant lymph nodes in the mediastinum based on node size is low. The most commonly used size criterion is a short axis diameter of 1 cm or greater on a transverse CT scan as an indicator of a “suspicious” lymph node. Whole-body PET scanning provides functional information on metabolic activity, is more sensitive and specific than chest CT scanning for staging lung cancer in the mediastinum ( Fig. 69.12 ), and can reveal occult metastases. Positive findings on PET scans can occur from nonmalignant conditions (e.g., infections), so tissue sampling to confirm the suspected malignancy is strongly recommended. MRI can be useful in selected circumstances such as superior sulcus tumors to rule out brachial plexus involvement but in general does not play a major role in NSCLC staging. Of course, abnormalities detected with any of the aforementioned imaging studies are not necessarily cancer. Unless overwhelming evidence of metastatic disease is present on imaging studies, curative-intent therapy should not be withheld based on imaging studies alone, but putative metastatic disease should be documented with tissue confirmation of malignancy.

Assessment of Extrathoracic Disease

The best initial predictor of metastatic disease remains a careful history and physical examination. If signs, symptoms, or findings from the physical examination suggest the presence of malignancy, then sequential imaging, starting with the most appropriate study based on the clues obtained during the clinical evaluation should be performed. If the findings from the clinical evaluation are negative, then additional imaging studies such as a CT scan of the head, a bone scan, or an abdominal CT scan are often unnecessary, and the search for metastatic disease is complete. Clinical findings suggestive of metastatic disease are listed in Table 69.9 . Patients with abnormal clinical evaluation findings should undergo imaging for extrathoracic metastases. Site-specific symptoms warrant directed evaluation of that site with the most appropriate study (e.g., CT scan of the head, bone scan, and abdominal CT scan). More controversial is how one should assess patients with known clinical stage III disease. Additional imaging may be required, given the high frequency of brain metastases, for example.

Solitary Pulmonary Nodule

The approach to a patient with a solitary pulmonary nodule is based on an estimate of the probability of cancer, determined according to the size of the nodule, the presence or absence of a history of smoking, the patient's age, and characteristics of the nodule's margins on CT images. Mayo Clinic investigators found that reported clinical characteristics (age, cigarette-smoking status, and prior cancer diagnosis ≥5 years ago) and three radiologic characteristics (diameter, spiculation, and upper lobe location) were independent predictors of malignancy. An efficient algorithm for assessing these lesions is outlined in Fig. 69.13 .

Presurgical Evaluation