68: Overview of Anatomy and Pathophysiology of Lung Cancer

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.

Squamous and SCLCs tend to arise in the central airways, whereas adenocarcinoma and large cell lung cancers tend to locate peripherally. SCLCs arise from neuroendocrine cells that are distributed in small numbers in the normal epithelium. There are four major types of neuroendocrine tumors: small-cell neuroendocrine, large cell neuroendocrine, and typical and atypical carcinoids. Typical carcinoids grow slowly and rarely spread beyond the lungs. Atypical carcinoids, which are rare, exhibit more rapid growth and are more likely to spread to other organs. The location of the carcinoid tumor (i.e., central, peripheral, or endobronchial) dictates the treatment approach; however, prognosis following resection for this tumor depends on an R0 resection (i.e., gross and microscopic complete tumor removal) and regional node dissection.

Squamous cell carcinomas arise from metaplastic squamous cells because squamous cells are absent from the normal epithelium. Adenocarcinomas arise from Clara cells or type 2 pneumocytes, the precursors of bronchioles and alveoli, respectively. Large cell cancers consist of poorly differentiated cells. Mucoepidermoid tumors arise from tracheobronchial mucous glands and have similar cellular features to mucoepidermoid tumors that originate in the salivary glands.

Identifying the specific histologic subtype confirms the diagnosis and can, in addition, provide important information with respect to molecular markers which may impact prognosis and treatment. However the more important distinction for clinical management and treatment outcomes, as mentioned above, is between SCLC and NSCLC. The chapters of Parts 11 and 12 focus on the surgical management of NSCLC.

Patients are candidates for surgical resection when there is a diagnosis or reasonable probability of NSCLC. Despite the disparate histology, these patients share similar prognosis and are managed with a unique staging system discussed below. Primary NSCLC tumors are often peripheral and grow more slowly than SCLC. Symptomatic manifestations of local disease in NSCLC include cough, hemoptysis, chest pain, dyspnea, wheezing, and pneumonia. Symptoms of locally advanced disease include hoarseness, phrenic nerve paralysis, dysphagia, stridor, superior vena cava syndrome, pleural effusion, pericardial effusion, Pancoast syndrome, evidence of lymphangitic spread, and cancer cachexia. Manifestations of extrathoracic spread include brain metastases, bone metastases, and spread to liver, adrenal glands, and intraabdominal lymph nodes. At clinical presentation, 60% to 75% of patients have cough, weight loss, or dyspnea. Hemoptysis, chest or bone pain, fever, and weakness occur slightly less often.³⁵ The physical examination foretells advanced disease if, among other signs, there is evidence of lymphadenopathy in the supraclavicular or cervical regions, percussion dullness suggesting a pleural effusion, or neck vein distention from superior vena cava obstruction (Table 68-4).³⁵

All cancers follow a progression from primary tumor to local invasion to systemic metastasis which is achieved through lymphatic, or hematogenous dissemination, or a combination of both. This is particularly relevant to thoracic malignancies because the pulmonary lymphatic system drains in an orderly progression along the bronchi to the hilum and then to the mediastinal nodes. This lends greater accuracy to both staging and prognostic correlation for cancer resections by anatomic lobar dissection with hilar and mediastinal node removal. The confounding difficulty is that skip metastases can occur in up to 25% of patients. The staging system used for NSCLC lung cancers⁹ defines the extent of disease based on the size of the tumor (T), the extent of nodal involvement (N) (Fig. 68-3), and the presence of distant metastases (M). The TNM concept was proposed originally by Denoix in the 1940s and later adopted by the American Joint Committee on Cancer and the International Union Against Cancer in 1986. The system has been revised several times in recent years.

The current version (edition 7) was revised by the International Association for the Study of Lung Cancer (IASLC) in 2010 resulting in several changes in TNM descriptors, which have caused a stage shift for certain patient groups. Caution is warranted when using this system in the clinical setting. There is a common misperception that a change in stage automatically yields a change in disease management. This belief is unfounded as the revised classification system does not provide any direct information about the superiority of one treatment approach over another. It does provide a superior tool for describing tumor characteristics. If properly used, it should aid comparative analysis in clinical research. However, only the results of clinical trials of particular treatments in defined patient populations can remain the basis for selecting optimal treatment approach (Fig. 68-4).

The TNM classification of malignant tumors consists of eight stages from early-stage carcinoma in situ to late-stage disease. These stages are shown in Figure 68-5 and the recommendations for the treatment of lung cancer are based on clinical outcomes which are stage specific. These are reviewed in Chapter 69. Stage I and II: early-stage lung cancer is treated by surgical resection. Patients with stage III tumors (i.e., locally advanced) may be possible surgical candidates on a case-by-case basis. This is primarily determined by the extent of local invasion with respect to T status and node status. Surgery for advanced local invasion with tumor infiltration of mediastinal structures such as the superior vena cava or the carina may be warranted if specific criteria are met. Surgery should be avoided for tumors involving unresectable mediastinal structures such as the great vessels, the esophagus, or the heart, or advanced multinodal mediastinal disease. An R0 resection (complete microscopic and macroscopic disease resection) is the goal of all stage I and II resections. Surgical resection for stage IV NSCLC (i.e., extensive metastatic spread) is usually contraindicated except in the uncommon scenario of surgery for oligometastatic disease, whereby resection with curative intent of proven solitary pulmonary metastases may be performed if specific criteria are met.

Surgical palliative procedures may occasionally be considered for patients in poor medical condition or advanced malignant conditions. Examples of this include the restoration of airway patency through bronchoscopic debridement of tumor, photodynamic therapy, airway stenting, or brachytherapy.

Noninvasive radiologic evaluation begins with a chest x-ray and chest CT scan through the adrenal glands to assess and determine the size of the lesion, involvement of surrounding structures, and overall resectability (Table 68-5). The sensitivity of CT scanning for detecting lung cancer is between 50% and 80%. MRI, once thought to hold promise as a diagnostic tool, is usually reserved for advanced anatomic problems when the results of CT scanning are ambiguous and for delineation of CNS metastases.³⁶ PET scanning has high sensitivity (range: 79%–95%) for detecting lung cancers, particularly distant metastatic disease, but a lower specificity for disease determination. Integrated CT/PET is both sensitive and specific, yielding 98% correct tumor staging compared with final histopathologic staging. These technologies are expanding, but the instruments are expensive and not as widely available as CT.³⁷ Although CT scanning remains the mainstay of clinical staging, CT scanning alone is inaccurate because it has a limited ability to determine mediastinal nodal involvement, chest wall invasion, mediastinal invasion, and malignancy of pleural effusions.^37,38

A number of staging and diagnostic procedures have evolved using bronchoscopy. Invasive bronchoscopic procedures include transbronchial needle aspiration, endobronchial ultrasound biopsy (EBUS-FNA), endoesophageal ultrasound fine-needle aspiration (EUS-FNA), and transbronchial and transesophageal needle biopsy. Although radiologic reconstructions of the bronchi and trachea are useful adjuncts to operative planning, bronchoscopy is recommended before every surgical resection as an aid to identifying anatomic abnormalities that might interfere with surgical resection and to confirm the accuracy of noninvasive study by determining the proximal extent of the tumor (i.e., distance from the carina). It is also valuable in identifying occult synchronous disease or anatomic variants of normal.

Invasive preresectional surgical staging, pioneered by the Thoracic Surgical Group of Toronto, is routine practice in many centers.^39,40 Mediastinal staging via mediastinoscopy was conceived originally to spare the morbidity of an exploratory thoracotomy.³⁹ It is used presently to document the nodal metastatic extent of lung cancer before surgical resection, as a guide to therapeutic decision making, and for restaging lung cancer (see Chapter 70).⁴¹ Selective lymph node station sampling via cervical mediastinoscopy may identify patients with minimal N2 disease (stage III) for neoadjuvant chemotherapy or multimodality protocols (e.g., chemotherapy, radiotherapy, and surgery). Many predict that the role of mediastinal staging in lung cancer will expand with the increasing availability and application of new diagnostic and therapeutic techniques, such as tissue biopsy for biomarker staging⁴² and tissue typing for oncogenic mutations⁴³ and drug-sensitivity testing.⁴⁴

Thoracoscopy is usually performed intraoperatively in patients who are identified with pleural effusions and for deep mediastinal nodal staging to confirm the presence or absence of cancer.

Meta-analysis of multiple clinical staging trials has been used to demonstrate the superiority of pathologically over clinically staged lung cancer. Survival in clinically staged IB patients (T2N0 disease) was only 75% at 1 year and 40% at 5 years.⁴⁵ In contrast, pathologically staged T₂N₀ disease yielded 90% survival at 1 year and 60% at 5 years,⁴⁵ highlighting the limitations of current CT technology. Mediastinoscopy is the gold standard for mediastinal node staging preresection. Noninvasive techniques used to supplant mediastinoscopy for mediastinal nodal staging results in a 10% error regardless of the noninvasive technique used.

Lesions located in specific lobes drain preferentially and predictably to specific nodal groups. Cervical mediastinoscopy is used to access nodes at the paratracheal levels (2R, 2L, 4R, 4L, 10R, and 10L) in addition to the subcarinal nodes at level 7. Anterior mediastinoscopy (also called parasternal mediastinoscopy) accesses lymph nodes at levels 5 and 6.

Thoracoscopy of the right hemithorax accesses the right paratracheal nodes (level 4R), inferior pulmonary ligament nodes (level 9), and subcarinal nodes (level 7). In the left hemithorax, thoracoscopy is used to access the aortopulmonary window nodes (levels 5 and 6) and the posterior hilar nodes.

Mediastinal staging by mediastinoscopy is commonly performed; it is also a safe and effective technique providing important histologic information with minimal morbidity. It is usually performed on an outpatient basis. It is currently indicated for patients with lung cancer suspected to have spread to the mediastinal nodes to provide accurate histologic lymph node staging and it is used to guide therapy. Patients not suspected of having mediastinal lymph node involvement may be staged with preoperative CT/PET and/or intraoperative thoracoscopic staging if appropriate to confirm the absence of mediastinal malignancy. The drawbacks to preresectional staging with mediastinoscopy are twofold: it requires general anesthesia and delays the surgical resection.

Preoperatively, all patients must undergo pulmonary function testing to assess their overall fitness for surgery and to predict postoperative outcome. These studies include forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and diffusion capacity of carbon monoxide (DLCO). The FEV₁ then is used to calculate the predicted postoperative FEV₁. A ppoFEV₁ of 0.8 to 1.0 L or more is desired for lung resection of any kind. This value is the product of FEV₁ and the percent of lung parenchyma that will remain after resection. Residual lung parenchyma can be estimated by the percent of remaining pulmonary lobes (x of 5) or remaining anatomic pulmonary segments (x of 18) or estimated percent of remaining ventilation or perfusion based on the V̇/Q̇ scan.

Depending on the size, location, and extent, the lesion may be resected using an anatomic (e.g., lobectomy, pneumonectomy, bilobectomy, or sleeve lobectomy) or nonanatomic (e.g., segmentectomy, wedge resection, precision cautery, or metastasectomy) resection (Chapters 70–79). These can all be performed by an open technique or with minimal access surgery. Lobectomy is the standard anatomic resection for NSCLC when the lesion occurs within the boundary of an anatomic lobe (see Chapter 71). The most common technique begins with a thoracotomy incision followed by hilar division of the lobar pulmonary arteries, draining pulmonary lobar veins, and associated bronchus. This is followed by meticulous dissection of hilar lymph nodes and lymphatics, which then are removed en bloc with the specimen lobe as a single unit. Alternatively, a sternotomy incision may be used for access to bilateral pleural spaces, mediastinum, and anterior hila in the presence of bilateral pulmonary nodules. This approach and muscle-sparing thoracotomies are associated with decreased postoperative pain. They may be used for early-stage I or II NSCLC.

Less-invasive pulmonary resections using video-assisted thoracic surgery technique, thoracoscopy, and other minimally invasive surgical techniques have improved the morbidity of surgical resection and afford surgery in patients with compromised pulmonary function The benefits of these techniques include shorter postoperative stay, reduced narcotic requirements for postoperative pain management, reduced shoulder dysfunction compared with patients undergoing thoracotomy, and greater patient satisfaction.

More than half of all cancers are diagnosed in patients aged 65 years or older, yet the risk of surgery is greatest in this group. Paradoxically, elderly patients also have a higher rate of early-stage cancer detection compared with younger adults. Lung-sparing resections using minimally invasive techniques, such as limited thoracoscopic wedge resection, are increasingly being offered to elderly patients (age >65 years) who have impaired or diminished respiratory function along with other comorbid conditions that make them unfit for pneumonectomy or lobectomy.⁴⁶ Postoperatively, pulmonary complications have been identified as the major cause of morbidity and mortality after surgery in elderly patients. It is reasonable to assume that a reduction in pulmonary complications through the use of less-invasive lung-sparing procedures will lead to a decrease in morbidity and mortality in the elderly age group.

The importance and value of accurate staging are evident in studies that report cumulative 5-year survival rates for NSCLC. Broadly estimated, average 5-year survival for all stages combined is 16%. This low survival rate has improved only minimally from earlier years despite multiple new modalities of treatment over the last 50 years. For stage I and II disease combined, it is 52%; however, for early-stage disease (stage IA) it may be as high as 80%. Examined individually, these reports demonstrate considerable variability. Reviews published before the 1997 revision of the TNM staging system differ from reports published thereafter, reflecting the expansion of stages I and II (i.e., stage IAB and IIAB) and the reassignment of certain stage III patients to stage IIB based on prognosis. A report published in 1995 estimated that the 5-year cumulative survival rate for patients with stage I (A + B) disease was 64.6%, and for those with stage II disease it was 41.2%.⁴⁷ Naruke et al.⁴⁸ and Mountain⁴⁵ independently evaluated 5-year survival in stage I (A + B) and stage II (A + B) disease using the 1997 revised IASLC. A summary of their findings reveals that the 5-year survival in stage I (A + B) disease combined is between 67% and 75%, whereas the limit of survival in stage IIB disease was no better than 38%. This reduced survival for stage II disease reflects the adverse effect of nodal metastasis, which portends aggressive tumor biology and behavior.

The importance of having a universally adopted international lung cancer staging system, as we do, is most evident when it comes to estimating survival, which is stage specific. It is also of great value when comparing outcomes of multimodality treatment protocols consisting of combinations of surgery, chemotherapy, radiotherapy, and other innovative treatments. Although surgery alone has been the mainstay of treatment for early-stage NSCLC, there is now compelling evidence from randomized trials that neoadjuvant and adjuvant chemotherapy will improve survival for appropriate stage II and IIIA NSCLC patients. There is as well clear evidence that adjuvant chemotherapy is helpful for stage IB tumors greater than 4 cm in diameter. Meaningful analysis of the numerous multimodality treatment protocols would be impossible without a universal staging system. This reliance is increased with the continuing expansion of new and divergent clinical methods to permit earlier lung cancer detection through screening, when surgery has the greatest chance for cure, or to tailor multimodality treatment protocols capable of preventing recurrence and improving survival.