Lung cancer killed an estimated 156,940 men and women in the United States in 2011, more than colon, breast, prostate, and pancreatic cancer combined.¹ More than 80% of these cases were caused by habitual or environmental exposure to tobacco smoke.² This clear-cut origin makes lung cancer a disease better suited to prevention than treatment. Non–tobacco-associated lung cancer (NTLC) is not a rare disease, however, with about 40,000 cases per year in the United States and an even greater percentage of total lung cancer cases in Asia. NTLC differs at a molecular level from tobacco-associated NSCLC, and these differences have clinical and therapeutic implications.

The reduction of lung cancer deaths in white American men over the past two decades has resulted more from the decrease in cigarette smoking after the publication of the U.S. Surgeon General’s report in 1964 than the real but modest advances in the effectiveness of therapy.

Although the results of current therapy are frustrating, they must not be met with nihilism. Small improvements in therapy help many individuals, comparable in years of life saved to the modest benefit seen with adjuvant therapy for patients with other common tumors, such as breast or colon cancer. Although avoiding tobacco use is the most efficient strategy for reducing lung cancer deaths, it is clearly worthwhile to optimize current therapeutic modalities of surgery, irradiation, and chemotherapy. Even if all current smokers quit smoking now, their previous carcinogen exposure would lead to another million or more cases of lung cancer. The need for effective treatment will continue in the foreseeable future.

Advances in multiple disciplines include tumor biology techniques that enable both identification and selective treatment of particular molecular entities within the broad spectrum of diseases termed lung cancer, imaging and treatment delivery technologies that better identify where to put the dose and deliver it there accurately and reproducibly (or adaptively to a target size and shape that is changing over time), and a growing willingness of specialists of all modalities to work collaboratively for their patients’ benefit.³ The development of interventions to facilitate such continuity of care and communication to patients is gaining attention.⁴ The key to improving treatment is the integration of diagnostic and treatment modalities by a team whose members are interested in lung cancer and its treatment, well versed in the application of the appropriate modalities, and able to combine them without undue bias.^5,⁶ The development of advocacy groups such as the Lung Cancer Alliance and their endorsement by groups such as the American Academy of Chest Physicians should hasten this becoming the standard of practice, as happened for patients with breast and prostate cancers.

Etiology and Epidemiology

More than 80% of cases of lung cancer can be attributed to carcinogens in tobacco smoke. Habitual and environmental exposures are clearly linked to lung cancer at levels ranging from descriptive epidemiology, characteristic patterns of oncogene and tumor suppressor gene mutations, and measurement of tobacco-associated carcinogens in the urine of individuals exposed to second-hand smoke.⁷^–¹⁰ Hecht and associates^11,¹² showed that nonsmokers, when exposed to side-stream smoke in concentrations comparable to those found in a smoky bar, excreted metabolites of tobacco-specific carcinogens in their urine. Pipe and cigar smokers have lower lung cancer rates than cigarette smokers, but these habits are far from innocuous, particularly in former cigarette smokers, who often continue to inhale.

The risk of lung cancer is related to the amount smoked daily and the duration of smoking, leading to the term pack-years as a measure of smoking exposure. When individuals quit smoking, their risk of lung cancer declines over at least a decade but remains higher than that of those who have never smoked.¹³^–¹⁵ Lung cancer incidence and death rates typically reflect smoking behavior from two to three decades previous. Examination of the respiratory epithelium of former smokers years after quitting shows persistence of telltale patterns of genetic and epigenetic change.^16,¹⁷ Once initiated, the process of lung carcinogenesis can proceed without continued smoke exposure.

Current epidemiologic efforts are devoted to better understanding the molecular determinants of risk distal to smoke exposure, including metabolic activation of procarcinogens, degradation and excretion of carcinogens, accurate repair of damaged DNA (or apoptotic execution of cells harboring DNA damage), and other less well understood mechanisms that result in the development of lung cancer in some but not all heavy smokers.¹⁸^–²⁰ Although no single genetic abnormality has been clearly implicated in causing lung cancer, there is considerable epidemiologic evidence for an inherited component of risk, particularly for cases of lung cancer diagnosed in younger individuals.²¹ Polymorphisms in a variety of enzymes involved in the metabolism of potential carcinogens, their detoxification, and in DNA repair enzymes have been associated with risk of lung cancer in a number of small studies of both smokers and nonsmokers but no clear risk pattern has been replicated in large populations.

Several recent studies have reported that a polymorphism in the nicotinic receptor gene cluster in the chromosome 15q24-25 region is strongly associated both with nicotine dependence and the development of chronic obstructive pulmonary disease (COPD) and lung cancer.²² Such associations have been seen in European, African, and Asian populations. Whether this locus is directly involved in tobacco carcinogenesis or indirectly mediated through strength of nicotine dependence is not yet clear.

In addition to tobacco smoke, many other substances have been implicated in causing lung cancer. Several industrial chemicals, particularly the chloromethyl ethers, have been associated with lung cancer. Exposure to asbestos and tobacco smoke produces lung cancer more frequently than either exposure alone. Exposure to inhaled radioactive substances by uranium miners or by individuals living in areas with high endogenous radon levels also increases risk.

Smokers with significant COPD are at significantly higher risk for lung cancer than individuals with similar smoke exposure without COPD.^23,²⁴ It is not known whether this reflects a common behavioral cause (e.g., deeper smoke inhalation, longer smoke retention) in these individuals or if there are differences in metabolism of components of tobacco smoke that increase the risk for COPD and lung cancer. Chronic inflammation has also been implicated in the pathogenesis of a variety of cancers.

Lung cancer has been reported in a number of patients with human immunodeficiency virus (HIV) infection, but there is no good evidence for a direct causative role. Lung cancer is not particularly common in individuals otherwise immunosuppressed, such as after organ transplantation. HIV-positive individuals with lung cancer tend to be younger than other patients, almost always have a history of heavy tobacco use, tend to present with advanced-stage disease (80% stage III and IV), show a predominance of adenocarcinomas, and have a poorer prognosis, even for those presenting with early-stage disease. The tolerance of these patients to treatment, particularly to aggressive chemoradiation may be compromised by limited hematologic reserve and development of severe mucositis during and after RT. Care must be taken to balance therapeutic aggressiveness and tolerance.

Human papillomavirus (HPV) infection, particularly with serotypes 16 and 18, has been associated with head and neck squamous cell carcinoma in humans, often without significant tobacco exposure.²⁵ Such tumors are biologically distinct from the typical tobacco-associated head and neck cancers and have a better outcome when treated with chemoradiation. Several studies have investigated the association of HPV with lung cancer and have found HPV in about 25% of lung cancers studied, with considerable geographic variation (about 15% in Europe and the Americas, about 35% in Asia, and as high as 80% in parts of Japan and Taiwan²⁶). It is not clear that the HPV virus is truly causative of lung cancer rather than associated with it, and this remains an area of active investigation. The therapeutic responsiveness and natural history of HPV-associated lung cancers has not been well characterized.

Although lung cancer used to be a predominately male disease, its incidence and death rates in women began to rise in the United States in the 1960s and the death rate from lung cancer in women has exceeded that of breast cancer since 1987.²⁷ In the United States, the incidence of lung cancer in men increased through the 20th century until leveling off and then starting to decline in the 1980s. In women, the incidence rose steadily through the latter part of the century but may now be starting to level off in the United States and Europe.

Although most cases of lung cancer occur in individuals with a history of tobacco use, lung cancer in those who have never smoked or in minimal smokers is far from a rare disease. It represents 15% to 20% of lung cancer seen in North America and Europe and up to 40% in parts of Asia. In the United States, deaths from non–tobacco-associated lung cancer amount to about 20,000 per year, ranking in the top five causes of cancer death. There are clear data that the clinical and molecular characteristics of lung cancer arising in persons who have never smoked or in minimal smokers are quite distinct from those of tobacco-associated lung cancer and warrant separate therapeutic strategies.28,29

Molecular Biology of Lung Cancer

Multiple genetic changes have been identified in lung cancers and cell lines derived from them and several distinct pathways of oncogenic development, both for squamous cell and several distinct varieties of adenocarcinoma, have been proposed.30,31 The morphologic and clinical differences between the various types of NSCLC are reflected in decidedly different patterns of oncogene and tumor suppressor genes modifications in these disease families. Although there are no absolute differences or characteristic mutations for either type in the way that the BCR-ABL translocation is relatively pathognomonic of chronic myeloid leukemia, some molecular abnormalities frequent in one histologic type are rare in another, and vice versa.

RAS

The RAS oncogene family contains three members, HRAS, KRAS, and NRAS, which encode membrane-associated proteins involved in mediation of signals arising from binding of ligands to cell membrane receptors such as epidermal growth factor receptors (EGFRs) to nuclear transcription factors.³² Mutation in several specific sites, including codons 12, 13, and 61, lead to constitutive activation of these signaling pathways.³³ In lung cancer, mutations are most commonly seen in KRAS.³⁴ They are most frequently seen in adenocarcinoma but are also seen in other NSCLC histologies.³⁵ They are seen almost exclusively in smokers and rarely if ever in those who have never smoked whose tumors contain EGFR mutations. Patients whose lung cancers contain mutated KRAS almost never respond to EGFR tyrosine kinase inhibition (EGFR-TKI), but it is not clear that they are resistant to cetuximab as is the situation in colorectal cancer.³⁶ The presence of mutated RAS genes has been an adverse prognostic factor in resected and advanced lung cancer in most series in which this has been assessed.³⁷ RAS mutations are rare in SCLC, and, when detected, they may represent an admixture of NSCLC elements or the development of an intermediate SCLC line.³⁸

MYC

The MYC gene products are nuclear transcription factors. Structural mutations are not reported in lung cancer, but amplification of copy number and overexpression are common in SCLC and uncommon in NSCLC with the exception of large cell neuroendocrine tumors. Amplification has been more commonly reported in cell lines from patients with clinically resistant tumors after chemotherapy, but the role of MYC amplification in de novo drug resistance is uncertain.³⁹^–⁴³

TP53

Abnormalities in TP53 function through deletion or mutation of the gene or overexpression of MDM2 leading to aberrant TP53 inactivation are among the most common genetically induced changes in human malignancies.⁴⁴ Mutations are reported in a high frequency in lung cancer, about 50% of NSCLCs, and 90% of SCLCs.^45,⁴⁶ Different patterns of mutation (e.g., ratio of transitions to transversions) are seen in smokers and in persons who have never smoked, suggesting different mutagens. Normal TP53 plays several key roles in determining cellular response to genetic damage, particularly whether cells enter growth arrest or apoptosis. There have been conflicting reports about the prognostic implications of abnormal TP53 function in lung cancer. For a number of chemotherapeutic agents and ionizing radiation, cells lacking normal TP53 function are resistant to apoptotic cell death, although the effect on overall cell survival is controversial.^47,⁴⁸

RB1

The RB1 gene–encoded product (RB) is a nuclear protein that undergoes cyclic phosphorylation and dephosphorylation during the cell cycle under the control of G₁ cyclins.^49,⁵⁰ RB regulates E2F1 transcription factor activation. Absence of normal function occurs in most SCLCs but only in about 10% of NSCLC lines examined.⁵¹^–⁵³

CDKN2A

Normally, CDKN2A (previously designated p16) regulates transcription through phosphorylation of the RB1 protein. Abnormalities of CDKN2A function are reported in a reciprocal fashion to those of RB1; they are common in NSCLC and rare in SCLC. Because either of these abnormalities can allow uncontrolled transcriptional activation through E2F, it is not surprising that they are not commonly found together.⁵⁴ Although mutations in either are common in lung cancer, these mutations have not been correlated with prognosis.

Growth Factors

Abnormalities in normal growth factor signaling pathways have been proposed as a common mechanism for the dysregulated cell growth in cancer. In lung cancer, several clear examples of this have been demonstrated to exist and have become targets for possible therapeutic intervention.

Epidermal Growth Factor Receptor

EGFR mediates a number of signaling pathways critical for cell growth, survival, and response to cytotoxins, including ionizing radiation and several chemotherapeutic agents. It is overexpressed in a variety of malignancies, and overexpression has been correlated with poorer clinical outcome and resistance to radiation. Clinical attempts to target this pathway have included monoclonal antibodies targeted to the extracellular domain of the receptor (C225, ABX) and low-molecular-weight compounds that bind the adenosine triphosphate (ATP) site and inhibit the tyrosine kinase activity of the receptor. About 10% of patients with NSCLC have mutations involving the ATP-binding pocket of the EGFR, which gives rise to more prolonged signaling activity in response to ligands such as epidermal growth factor (EGF) or transforming growth factor–beta and causes them to bind these inhibitors more tightly.⁵⁵^–⁵⁷ Such activation mutations are seen primarily in individuals with no or minimal smoking history and in Asian women and are more common in adenocarcinomas than squamous cell carcinoma. Patients whose tumors have these mutations are likely to have significant objective responses to treatment with these compounds, but it is postulated that patients with wild-type, overexpressed EGFR are more likely to show a response of growth restraint but not regression. The relative importance of mutation and overexpression of EGFR in predicting outcome of treatment with EGFR-TKI such as erlotinib is a subject of controversy and active research.^58,59,60

ERBB2

Overexpression of ERBB2 (formally HER2) is reported in NSCLC, particularly adenocarcinoma, and it is correlated with decreased survival of patients with resected disease.^61,⁶² The degree of overexpression is typically much less than seen in cancer of the breast, with few lung cancer patients showing 3+ staining. Trials of monoclonal antibodies directed against ERBB2 in unselected NSCLC patients have shown relatively little activity whether used alone or in combination with cytotoxic chemotherapy.⁶³

In addition to overexpression of wild-type ERBB2, activating point mutations have been described in a number of patients with NSCLC.⁶⁴ These patients, about 5% of all with NSCLC or 15% of those with adenocarcinoma, may be more sensitive to therapies directed against ERBB2-mediated signaling and warrant further study with these agents, as may also be appropriate for patients with unmutated but highly overexpressed (3+ by immunohistochemical staining) ERBB2.⁵⁹

Recently, fusion genes that produce atypically activated transcription factors or kinases, long known in leukemias and sarcomas, have been described in a number of solid tumors.⁶⁵ Fusion of EML4 and ALK has been described in a subset of patients with NSCLC.⁶⁶ Patients with EML4-ALK are typically young and light smokers or persons who have never smoked with adenocarcinoma. Because these clinical features also are more commonly seen in patients with EGFR mutations but patients with EML4-ALK mutations are not sensitive to TKI targeting EGFRs such as gefitinib or erlotinib, it becomes increasingly important to select targeted therapies on the basis of molecular profiling of individual tumors rather than population statistics.⁶⁷ Inhibitors of the ALK kinase have shown significant activity in vitro and in early clinical trials and are entering trials comparing them with conventional cytotoxic agents in patients with EML4-ALK mutations.⁶⁸

Early Detection and Prevention

Fewer than 20% of lung cancer patients in the United States are diagnosed with localized (stage I) disease. The poor survival of patients with symptomatic lung cancer prompted efforts to diagnose the disease in asymptomatic individuals. The U.S. National Cancer Institute (NCI) sponsored several trials in the 1970s comparing active screening using annual chest radiography and sputum cytology with “routine” medical care.^69,⁷⁰ These studies showed increased detection of localized disease in the screened populations, with higher rates of resectability but no decrease in mortality. This led to recommendations from the American Cancer Society to abandon routine screening for lung cancer by the methods used and in the populations studied (warranted by the data) and to an unwarranted pessimism about early diagnosis in general.

Since these trials, important demographic and technologic changes have occurred. Lung cancer is increasingly a disease of women.⁷¹ Lung cancer has also increasingly become a disease of former smokers. Several large centers have reported that more than one half of their lung cancer patients are former (i.e., more than 1 year since cessation) rather than current smokers.⁷² This change has key implications for therapeutic interventions and in the possibility of enlisting this population, who have already demonstrated a high degree of motivation by quitting smoking, in studies of early detection and chemoprevention.

Silvestri and associates ⁷³ have reviewed the current status of screening for lung cancer in the light of this changing demography and proposed 10 essential criteria for a successful screening program: “The disease must have serious consequences and be readily detectable in the preclinical phase. The test should have a high accuracy, detect the disease before a critical point, cause little morbidity, be available and affordable, and result in little overdiagnosis. Finally, treatment for the disease must exist, and it must be effective before symptoms occur, with little risk or morbidity.”

Computed Tomography–Based Screening Studies

The availability of fast high-resolution computed tomography (CT) has prompted a new round of screening trials.⁷⁴ CT is more sensitive in detecting pulmonary nodules in asymptomatic individuals than chest radiography. The percentage of detected nodules ultimately proved to be cancerous has varied considerably between different series, in part owing to the background frequency of conditions such as endemic fungal infections that may give rise to benign pulmonary nodules. Most series have shown a shift to earlier stage at diagnosis for screened patients compared with historical controls, which is potentially a marker for improved survival. However, others have argued that tumors detected through screening are likely to have a different and more indolent biology than other tumors and that only prospective trials can determine whether CT screening reduces overall or tumor-specific mortality. Several large trials of screening CT have been completed in recent years to determine whether there is a reduction in overall mortality. Results are pending, and the current National Comprehensive Cancer Network (NCCN) and American College of Chest Physicians (ACCP) recommendations do not advocate screening for any groups.⁷⁵

Cytologic and Molecular Screening

Advances in molecular technology offer the promise of detecting malignant changes in exfoliated cells well before morphologic changes appear. Tockman and associates ⁷⁶ have shown that with monoclonal antibody staining using sera developed against SCLC and NSCLC lines, sputum cells showing atypia could predict which patients were going to develop frank malignancy with a lead time of about 2 years. This technique is being studied further in a prospective trial of patients who have undergone resection of a stage I NSCLC and are at high risk for local recurrence and development of a second primary lung cancer. Mao and co-workers⁷⁷ reported similar findings using probes for mutations of KRAS and TP53 genes. Mills and colleagues⁷⁸ also reported detection of KRAS mutations in fluid obtained at bronchioalveolar lavage. Others have reported the ability to detect EGFR mutations in circulating tumor cells or DNA fragments.^79,80 These findings, reported initially in retrospective pilot trials, are being validated in large, prospective trials seeking to detect second malignancies in patients curatively resected for their first lung cancers. Examination of the bronchial epithelium reveals multiple areas of dysplasia and carcinoma in many of these patients at the time of their initial diagnosis, and the risk of a second invasive malignancy is about 3% per year.

Autofluorescence bronchoscopy has been used to examine the tracheobronchial tree and look for early neoplastic or preneoplastic lesions.⁸¹ This approach complements CT screening, which primarily detects peripheral lesions and has poor sensitivity for small endobronchial lesions.⁸²

One reasonable interpretation of the results of the NCI-sponsored early-detection trials is that although they were successful in detecting disease earlier than would have been done without screening, this “early” disease was still quite advanced in terms of the natural history of the disease. Key events such as the ability of tumor cells to metastasize, induce angiogenesis, and develop resistance to chemotherapeutic agents were likely to have occurred earlier in their history. Recognition of the long promotion period in the development of lung cancer suggests that a more fruitful approach would be to detect intermediate points in this process, to screen for carcinogenesis instead of cancer.⁸³

Screening is not innocuous. In addition to the small but finite radiation hazard from CT scans, patients undergoing screening are at risk for complications of further testing and intervention associated with false-positive screen findings. Patients should be made aware of these potential downsides of screening before making decisions to be screened outside the context of a clinical trial.

At present the techniques available for detection of early lung cancer are undergoing rapid development and may lead to the development of effective screening techniques, but no regimen (target population, tests, frequency) has been shown to improve overall mortality of the screened population. Until this has been shown, the recommendation of the ACCP that “individuals undergo screening only when it is administered as a component of a well designed clinical trial with appropriate human subjects’ protection” seems quite appropriate.⁷⁵

Chemoprevention

Several classes of compounds have been investigated as candidate agents for lung cancer prevention.⁸⁴ Epidemiologic data show a higher incidence of lung cancer in populations with low dietary intake of retinoids and carotenoids. Deficiencies of these agents can lead to squamous metaplasia in animal models. Provision of exogenous vitamin A to animals that have developed metaplasia or atypia can lead to morphologic normalization of the epithelium.

Several trials of retinoids have been conducted in patients at high risk for lung cancer. Hong and associates ^85,⁸⁶ randomized patients with treated cancers of the head and neck to 13-cis-retinoic acid or placebo and found that although the recurrence rates of the initial lesion were unchanged, the treated group had a significantly reduced incidence of second primary tumors, particularly of the head, neck, lung, and esophagus. Pastorino and associates⁸⁷ conducted a similar trial in resected lung cancer patients using retinoyl palmitate and observed fewer second primary tumors and a borderline improvement in OS. However, larger, prospective, confirmatory trials testing isotretinoin or retinyl palmitate and N-acetylcysteine^88,⁸⁹ have failed to confirm the initial promise of earlier trials. To further complicate matters, several trials of β-carotene as a chemopreventive agent⁹⁰ have observed increased rates of cancer in populations of individuals who continue to smoke.

The epidemiologic correlation between reduced consumption of foods rich in carotenoids and an increased risk of lung cancer in smokers and the laboratory data showing a protective effect of β-carotene against lung carcinogenesis led to two large chemoprevention trials.⁹¹^–⁹⁴ In Finland, a trial of placebo versus β-carotene or α-tocopherol (i.e., vitamin E), or both,⁹⁵ showed increased rates of and death from lung cancer in subjects receiving β-carotene. Participants in this trial were predominantly actively smoking males. In the United States, a trial of β-carotene (CARET) was closed prematurely when interim analysis also showed an increased incidence of lung cancer in the treated arm of the study.⁹⁶ The increased risk of lung cancer incidence and death of lung cancer persisted even after further administration of β-carotene was discontinued.^97,⁹⁸ Although the popular interpretation of these trials has been negative, they offer clear proof of the principle that human lung carcinogenesis is a dynamic process amenable to pharmacologic manipulation. They also reinforce the basic principle that clever ideas must be tested in careful trials before becoming standard of practice. No agent has yet been recognized and confirmed as an effective chemopreventive agent for lung, head, or neck cancers, and an untreated control group remains appropriate and essential for future trials.

Selenium is a trace mineral whose presence in the soil varies considerably with geography. Selenium deficiency in animals can produce premalignant changes. Epidemiologic studies have suggested correlation between low dietary intake and cancer of a number of sites. With these considerations in mind, Clark and colleagues ⁹⁹ performed a trial of selenium supplementation versus placebo in subjects with a history of multiple skin cancers, with a reduction in subsequent skin cancers as the designed trial outcome. Such a reduction was not seen, but the number of cases of lung cancer in the treated group was one half of that in the control group. Because multiple secondary comparisons were made in the trial, this observation might reflect chance, and a confirmatory trial to compare selenium with placebo in patients with resected stage I NSCLC has been conducted in North America, with results pending.

One limitation of the chemoprevention trials is that the candidate agents were administered systemically with the attendant toxicities associated with this approach. An approach of delivering agents directly to the bronchial epithelium, where the smoke went and where carcinogenesis occurs, is appealing and is being explored with the development of agents deliverable by aerosol.¹⁰⁰

At present no agent or combination of agents has been proven to delay or prevent the development of lung cancer of any histology in an at-risk population of current or former smokers. Although a number of the candidate agents (e.g., selenium) are of relatively low toxicity, the surprising result of increased lung cancer incidence in some retinoid trials as well as the increased risk of diabetes in patients taking selenium in a prostate cancer chemoprevention trial suggest caution rather than therapeutic adventurism in this area.¹⁰¹ The ACCP currently recommends that no agent be used for lung cancer chemoprevention outside of a clinical trial.¹⁰²

Pathology and Pathways of Spread

The respiratory epithelium has a total surface area about the size of a tennis court. It may be divided functionally and pathologically into three zones. From the trachea through the major bronchi the normal lining is made of squamous cells with interspersed neuroendocrine cells, which appear most commonly at airway bifurcations. Terminal alveoli are lined predominantly with type I and type II pneumocytes. Intermediate bronchi and bronchioles show a transition between squamous and adenomatous lining cells and a corresponding mixture of tumor types. The exposure of this large organ to a common set of inhaled toxins sets in process a widespread set of molecular and subsequent morphologic changes. Slaughter and associates,¹⁰³ who first observed this phenomenon in patients with multiple primary tumors of the head and neck, referred to it as field cancerization. Auerbach and colleagues¹⁰⁴ described similar widespread changes in the lungs of smokers with lung cancer, and Saccomano and colleagues¹⁰⁵ described a pattern of progressive degrees of cytologic atypia leading to frankly invasive carcinoma. The practical consequence of this is that patients who develop one neoplasm of the upper aerodigestive tract (i.e., head, neck, lung, and esophagus), if treated successfully, remain at substantial risk for developing a second or subsequent primary tumor. For patients with resected stage I NSCLC, this risk is on the order of 2% to 3% per year for at least 10 years after treatment of the first cancer.^88,^106,¹⁰⁷ It can sometimes be difficult to distinguish second primary tumors from local recurrences or metastases; differences in histology location, and presence of adjacent mucosal abnormalities have been proposed as criteria. Molecular markers may allow for fingerprinting by characteristic mutations at such sites as KRAS or TP53 (which are known to have different mutational spectra in different parts of the aerodigestive tract), although it still sometimes may be difficult to distinguish between separate primary tumors and clonal variation of a metastasis and most cells in its primary tumor. Recent data have suggested, however, that multifocal lung cancers may share a common clonal origin.^108,109

Lung cancer is divided into two major histologic subgroups: SCLC and the combination of squamous cell carcinoma, adenocarcinoma, and large cell undifferentiated carcinoma considered collectively as NSCLC. In the past, SCLC and NSCLC were viewed as quite different diseases, but there is increasing convergence in modern therapeutic approaches with the understanding that both are usually disseminated diseases that manifest as substantial bulk disease in the chest, for which successful treatment requires systemic and locoregional therapies.

In addition to cell type and anatomic stage, a variety of molecular prognostic factors have been proposed to provide further prognostic or predictive information in lung cancer (Table 42-1). These include measures of cell proliferation (e.g., S-phase fraction, proliferating-cell nuclear antigen [PCNA], Ki-67, potential doubling time [T_pot]), mutated or overexpressed oncogenes and/or tumor suppressor genes (e.g., KRAS, TP53, ERBB2, BCL2), cell surface antigens (i.e., blood type antigens and their precursors), and induction of angiogenesis. Most of these have been proposed on the basis of small series of patients treated in a nonuniform fashion, and they often are based on univariate rather than multivariate analysis. Proper validation of these will require prospective study in large series of patients staged, treated, and observed in a uniform fashion.¹¹⁰ It is likely that patterns of expression of multiple markers as assessed by genomic or proteomic analysis will more successfully predict prognosis, as has been shown for breast cancer and intermediate-grade lymphomas. Small series have reported the success of such profiling in lung adenocarcinomas, but large validation series in uniformly treated patient groups are awaited.¹¹¹ Such profiling may also be useful in determining those patients at greatest risk for specific patterns of metastatic spread, such as to the brain, for whom particular targeted adjuvant therapies such as prophylactic cranial irradiation may be more appropriate than in an unselected population.

TABLE 42-1 Proposed Prognostic and Predictive Factors for Non–Small Cell Lung Cancer

Factor	Comment
Tumor volume	Partially incorporated into new TNM classification
Number of nodal sites	—
Clinically evident nodal involvement	Identified preoperatively as distinct from microscopic nodal involvement
Extranodal extension	May be prognostic for local recurrence and predictive of impact of postoperative radiation therapy on survival
IHC detection of nodal metastases	Nodes negative by H&E but positive by IHC
Histology	Predictive of response and toxicity with some agents
Ploidy	—
Proliferative rate (labeling index, Ki-67, T_POT	—
KRAS mutation	Predictive of resistance to EGFR-TKI
3p deletion	—
TP53 mutation or overexpression	—
Angiogenesis (microvessel density)	—
Vascular endothelial growth factor (VEGF) overexpression	—
Epidermal growth factor receptor (EGFR) overexpression and/or mutation	Mutation predictive for response to EGFR-TKI
ERBB2 (HER/neu) oncogene expression and/or mutation	Possibly predictive for response to trastuzumab
EML4-ALK	Possibly predictive for response to ALK-TKI

H&E, hematoxylin-eosin; IHC, immunohistochemical; TKI, tyrosine kinase inhibition.

Adapted from Wagner H, Bonomi P: Preoperative and postoperative therapy for non–small cell lung cancer. In Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia, WB Saunders, 1995, pp 147-163.

The outcome of an individual case of lung cancer is a function of the histology and stage of the disease and the status of the host. Host factors reflect both tumor burden not yet demonstrable by imaging techniques and the individual’s ability to withstand the morbidity of treatment. In many patients with lung cancer, physiologic function is impaired, in part owing to the advanced age of many patients (median age of diagnosis is in the seventh decade) and the frequency of other illnesses, such as COPD and cardiac disease, which are also smoking related.

Lung cancer spreads through regional lymphatic vessels within the lung to the hilar and paratracheal nodes, which drain to the supraclavicular fossae and, to a lesser degree, the upper abdomen (Fig. 42-1). The patterns of nodal spread are partially predictable on the basis of tumor size, histology, and proximity to central airways. Involvement most often begins with intrapulmonary nodes, extends centrally to the hilum, and then extends to the mediastinum. However, noncontiguous “skip” metastases are well described. Although nodal involvement can usually be detected by preoperative CT, even for T1 primary tumors, the incidence of clinically unsuspected nodal metastases can be as high as 15% to 20% for peripheral adenocarcinomas.^112,¹¹³