CHAPTER 35: NEOPLASMS OF THE LUNG

Lung cancer is largely a disease of modern humans and was considered quite rare before 1900, with fewer than 400 cases described in the medical literature. However, by the mid-twentieth century, lung cancer had become epidemic and firmly established as the leading cause of cancer-related death in North America and Europe, killing more than three times as many men as prostate cancer and nearly twice as many women as breast cancer. This fact is particularly distressing since lung cancer is one of the most preventable of all of the common malignancies. Tobacco consumption is the primary cause of lung cancer, a fact firmly established in the mid-twentieth century and codified with the release of the U.S. Surgeon General's 1964 report on the health effects of tobacco smoking. Following the report, cigarette use started to decline in North America and parts of Europe and with it so did the incidence of lung cancer. To date, the decline in lung cancer is seen most clearly in men; only recently has the decline become apparent among women in the United States. Unfortunately, in many parts of the world, especially in countries with developing economies, cigarette use continues to increase, and along with it, the incidence of lung cancers is also rising. While tobacco smoking remains the primary cause of lung cancer worldwide, more than 60% of new lung cancers occur in never smokers (smoked <100 cigarettes per lifetime) or former smokers (smoked ≥100 cigarettes per lifetime, quit ≥1 year), many of whom quit decades ago. Moreover, 1 in 5 women and 1 in 12 men diagnosed with lung cancer have never smoked. Given the magnitude of the problem, it is incumbent that every internist has a broad knowledge of lung cancer and its management.

Lung cancer is the most common cause of cancer death among American men and women. It was predicted that more than 220,000 individuals would be diagnosed with lung cancer in the United States in 2010. The incidence of lung cancer peaked among men in the late 1980s and has plateaued in women. Lung cancer is rare before age 40 years, with rates increasing until age 80 years, after which the rate tapers off. The projected lifetime probability of developing lung cancer is estimated to be approximately 8% among males and approximately 6% among females. The incidence of lung cancer varies by racial and ethnic group, with the highest age-adjusted incidence rates among African Americans. The excess in age-adjusted rates among African Americans occurs only among men, but age-specific rates show that before age 50 years, mortality from lung cancer is more than 25% higher among African American than white women. Incidence and mortality rates among Hispanic and Native and Asian Americans are approximately 40–50% those of whites.

RISK FACTORS

While the large majority (80–90%) of lung cancers is caused by cigarette smoking, several other factors have been implicated, although none to the extent of tobacco. Cigarette smokers have a 10-fold or greater increase in risk of this cancer compared with those who have never smoked. A deep sequencing study suggested that one genetic mutation is induced for every 15 cigarettes smoked. The risk of lung cancer is lower among persons who quit smoking than among those who continue smoking; former smokers have a ninefold increased risk of developing lung cancer compared with men who have never smoked versus the 20-fold excess in those who continue to smoke. The size of the risk reduction increases with the length of time the person has quit smoking, although generally even long-term former smokers have higher risks of lung cancer than those who never smoked. Cigarette smoking increases the risk of all the major lung cancer cell types. Environmental tobacco smoke (ETS) or secondhand smoke is also an established cause of lung cancer. The risk from ETS is less than from active smoking, with a 20–30% increase in lung cancer observed among never smokers married for many years to smokers compared with the 2000% increase among continuing active smokers.

While cigarette smoking is the dominant cause of lung cancer, several other risk factors have been identified, including occupational exposures to asbestos, arsenic, bischloromethyl ether, hexavalent chromium, mustard gas, nickel (as in certain nickel-refining processes), and polycyclic aromatic hydrocarbons. Occupational studies also have provided insight into possible mechanisms of lung cancer induction. For example, the risk of lung cancer among asbestos-exposed workers is increased primarily among 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. Several other occupational exposures have been associated with increased rates of lung cancer, but the causal nature of the association is not as clear.

The risk of lung cancer appears higher among individuals with low fruit and vegetable intake during adulthood. This observation led to hypotheses that specific nutrients, in particular retinoids and carotenoids, might have chemopreventive effects for lung cancer. However, randomized trials failed to validate this hypothesis. In fact, studies found the incidence of lung cancer was increased among smokers with supplementation. Ionizing radiation is also an established lung carcinogen, most convincingly demonstrated from studies showing increased rates of lung cancer among survivors of the atom bombs dropped on Hiroshima and Nagasaki and large excesses among workers exposed to alpha irradiation from radon in underground uranium mining. Prolonged exposure to low-level radon in homes might impart a risk of lung cancer equal or greater than that of ETS. Prior lung diseases such as chronic bronchitis, emphysema, and tuberculosis have been linked to increased risks of lung cancer as well.

Smoking cessation

Given the undeniable link between cigarette smoking and lung cancer (not even addressing other tobacco-related illnesses), physicians must promote tobacco abstinence. Physicians also must help their patients who smoke to stop smoking. Smoking cessation, even well into middle age, can minimize an individual's subsequent risk of lung cancer. Stopping tobacco use before middle age avoids more than 90% of the lung cancer risk attributable to tobacco. However, little health benefit is derived from just "cutting back." Importantly, smoking cessation can even be beneficial in individuals with an established diagnosis of lung cancer, as it is associated with improved survival, fewer side effects from therapy, and an overall improvement in quality of life. Moreover, smoking can alter the metabolism of many chemotherapy drugs, potentially adversely altering the toxicities and therapeutic benefits of the agents. Consequently, it is important to promote smoking cessation even after the diagnosis of lung cancer is established.

Physicians need to understand the essential elements of smoking cessation therapy. The individual must want to stop smoking and must be willing to work hard to achieve the goal of smoking abstinence. Self-help strategies alone only marginally affect quit rates, whereas individual and combined pharmacotherapies in combination with counseling can significantly increase rates of cessation. Therapy with an antidepressant (e.g., bupropion) or nicotine replacement therapy (varenicline, an α₄β₂ nicotinic acetylcholine receptor partial agonist), are approved by the U.S. Food and Drug Administration (FDA) as first-line treatments for nicotine dependence. However, both drugs have been reported to increase suicidal ideation and must be used with caution. In a randomized trial, varenicline was more efficacious than bupropion or placebo. Prolonged use of varenicline beyond the initial induction phase proved useful in maintaining smoking abstinence. Clonidine and nortriptyline are recommended as second-line treatments.

Inherited predisposition to lung cancer

Exposure to environmental carcinogens, such as those found in tobacco smoke, induce or facilitate the transformation from bronchoepithelial cells to the malignant phenotype. The contribution of carcinogens on transformation is modulated by polymorphic variations in genes that affect aspects of carcinogen metabolism. Certain genetic polymorphisms of the P450 enzyme system, specifically CYP1A1, or chromosome fragility are associated with the development of lung cancer. These genetic variations occur at relatively high frequency in the population, but their contribution to an individual's lung cancer risk is generally low. However, because of their population frequency, the overall impact on lung cancer risk could be high. In addition, environmental factors, as modified by inherited modulators, likely affect specific genes by deregulating important pathways to enable the cancer phenotype.

First-degree relatives of lung cancer probands have a two- to threefold excess risk of lung cancer and other cancers, many of which are not smoking-related. These data suggest that specific genes and/or genetic variants may contribute to susceptibility to lung cancer. However, very few such genes have yet been identified. Individuals with inherited mutations in RB (patients with retinoblastoma living to adulthood) and p53 (Li-Fraumeni syndrome) genes may develop lung cancer. Three genetic loci for lung cancer risk have been identified by genomewide association studies, including 5p15 (TERT-CLPTM1L), 15q25(CHRNA5-CHRNA-3 nicotinic acetylcholine receptor subunits), and 6p21 (BAT3-MSH5). A rare germline mutation (T790M) involving the epidermal growth factor receptor (EGF-R) maybe be linked to lung cancer susceptibility in never smokers. Currently, however, no molecular criteria are used to select patients for more intense screening regimens or for specific chemopreventive strategies.

PATHOLOGY

The term lung cancer is used for tumors arising from the respiratory epithelium (bronchi, bronchioles, and alveoli). Mesotheliomas, lymphomas, and stromal tumors (sarcomas) are distinct from epithelial lung cancers. According to the World Health Organization classification, epithelial lung cancers consist of four major cell types: small cell lung cancer (SCLC) and the so-called non–small cell lung cancer (NSCLC) histologies including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (Fig. 35-1). These four histologies account for approximately 90% of all epithelial lung cancers. The remainder include undifferentiated carcinomas, carcinoids, bronchial gland tumors (including adenoid cystic carcinomas and mucoepidermoid tumors), and rarer tumor types. Tumors may occur as single or mixed-type histology.

All histologic types of lung cancer can be found in current and former smokers. Historically, the histologies associated with heavy tobacco use are squamous and small cell carcinomas. Squamous carcinoma was the most commonly diagnosed form of NSCLC; however, with the steady decline in cigarette consumption over the past four decades and changes in cigarette manufacturing (including use of different types of filters), adenocarcinoma has replaced squamous cell carcinoma as the most frequent histologic subtype in North America. The incidence of small cell carcinoma is also on the decline. In lifetime never smokers, all histologic forms of lung cancer can be found, although adenocarcinoma tends to predominate. Among women and young adults (<60 years), adenocarcinoma tends also to be the most common form of lung cancer.

Small cell carcinoma is a poorly differentiated neuroendocrine tumor that tends to occur as a central mass with endobronchial growth and is strongly associated with smoking. Small cell carcinoma cells have scant cytoplasm, small hyperchromatic nuclei with a fine ("salt and pepper") chromatin pattern, and prominent nucleoli. Tumors might be arranged in diffuse sheets of cells or may show neuroendocrine patterns such as rosettes, trabeculae, or peripheral palisading of cells at the periphery of nests. There is often widespread cellular necrosis. Small cell carcinomas, more often than non–small cell carcinomas, may produce specific peptide hormones such as adrenocorticotrophic hormone (ACTH), arginine vasopressin (AVP), atrial natriuretic factor (ANF), and gastrin-releasing peptide (GRP). These hormones may be associated with distinctive paraneoplastic syndromes that prompt workup and eventual diagnosis (Chap. 52).

Squamous cell carcinomas of the lung are morphologically identical to extrapulmonary (i.e., head and neck) squamous cell carcinomas and require clinical correlation to differentiate. These tumors tend to occur centrally and are classically associated with a history of smoking. Histologically, the most common pattern is that of an infiltrating nest of tumor cells that lack intercellular bridges. Keratin can usually be seen when present.

Adenocarcinomas often occur in more peripheral lung locations and may be associated with a history of smoking. However, adenocarcinomas are the most common type of lung cancer occurring in never smokers. Histologically, the tissue may contain the presence of glands, papillary structure, bronchioloalveolar pattern, cellular mucin, or solid pattern if poorly differentiated. Variants of adenocarcinomas include signet-ring, clear cell, and mucinous and fetal adenocarcinomas. Bronchioloalveolar carcinoma (BAC) is a subtype of adenocarcinoma that grows along the alveoli without invasion and can present radiographically as a single mass, as a diffuse multinodular lesion, as a fluffy infiltrate, and on screening computed tomography (CT) scans as a "ground-glass" opacity (GGO). Pure BAC is relatively rare. More common is adenocarcinoma with BAC features. BAC may present in a mucinous form, which tends to be multicentric, and a nonmucinous form, which tends to be solitary.

Large cell carcinomas tend to occur peripherally and are defined as poorly differentiated carcinomas of the lung composed of larger malignant cells without evidence of squamous, glandular differentiation, or features of small cell carcinoma by light microscopy. These tumors usually consist of sheets of large malignant cells, often with associated necrosis. Cytologically, the tumor is also arranged in syncytial groups and single cells. Variants of large cell, carcinoma include basaloid carcinoma, which may present as an endobronchial lesion and may resemble a high-grade neuroendocrine tumor, and lymphoepithelioma-like carcinoma, which is similar to the same-named tumor of other sites and is Epstein-Barr virus–related.

Historically, for treatment and prognostication purposes, the major distinction has been between SCLC and NSCLC, as these tumors have quite different natural histories and therapeutic approaches. SCLC is typically widely disseminated at diagnosis. Even if localized, it is rarely curable by surgery. By contrast, NSCLC can be potentially cured by resection in up to 30% of cases. Small cell cancers tend to respond more favorably to traditional cytotoxic chemotherapy agents. Intrinsic drug resistance is the norm for both SCLC and NSCLC. As knowledge of tumor biology improves, more sophisticated classification schemas are under development, including ones based in part on the presence of specific mutations and molecular alterations (Fig. 35-2). Recognition of these molecular distinctions may help guide therapy in the future.

IMMUNOHISTOCHEMISTRY

The diagnosis of lung cancer most often rests on the morphologic or cytologic features correlated with clinical and radiographic findings. Immunohistochemistry may be used to verify neuroendocrine differentiation within a tumor, with markers such as neuron-specific enolase (NSE), CD56 or neural cell adhesion molecule (NCAM), synaptophysin, chromogranin, and Leu7 (Table 35-1). Immunohistochemistry is also helpful in differentiating primary from metastatic adenocarcinomas. Thyroid transcription factor 1 (TTF-1), identified in tumors of thyroid and pulmonary origin, is positive in more than 70% of pulmonary adenocarcinomas and is a reliable indicator of primary lung cancer, provided a thyroid primary has been excluded. A negative TTF-1 result, however, does not exclude the possibility of a lung primary. TTF-1 is also positive in neuroendocrine tumors of pulmonary and extrapulmonary origin. Cytokeratins 7 and 20 used in combination can help narrow the differential diagnosis; nonsquamous NSCLC, SCLC, and mesothelioma may stain positive for CK7 and negative for CK20, while squamous cell lung cancer will be both CK7 and CK20 negative. Mesothelioma can be easily identified ultrastructurally, but it has historically been difficult to differentiate from adenocarcinoma through morphology and immunohistochemical staining. Several markers in the past few years have proven to be more helpful, including CK5/6, calretinin, and Wilms' tumor gene 1 (WT-1), all of which show positivity in mesothelioma.

MOLECULAR PATHOGENESIS

Cancer is a disease involving dynamic changes in the genome. As proposed by Hanahan and Weinberg, virtually all cancer cells acquire six hallmark capabilities: self-sufficiency in growth signals, insensitivity to antigrowth signals, evading apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis. The order in which these hallmark capabilities are acquired appears quite variable and can differ from tumor to tumor. Events leading to acquisition of these hallmarks can vary widely, although broadly, cancers arise as a result of accumulations of gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes. Further complicating the study of lung cancer, the sequence of events that lead to disease is clearly different for the various histopathologic entities.

The exact cell of origin for lung cancers is not known. Whether one cell of origin leads to all histologic forms of lung cancer is unclear. However, at least for lung adenocarcinoma, type II epithelial cells (or alveolar epithelial cells) have the capacity to give rise to tumors. For SCLC, cells of neuroendocrine origin have been implicated as precursors.

For cancers in general, one theory holds that a small subset of the cells within a tumor (i.e., "stem cells") are responsible for the full malignant behavior of the tumor. As part of this concept, the large bulk of the cells in a cancer are "offspring" of these cancer stem cells. While clonally related to the cancer stem cell subpopulation, most cells by themselves cannot regenerate the full malignant phenotype. The stem cell concept may explain the failure of standard medical therapies to eradicate lung cancers, even when there is a clinical complete response. Disease recurs because therapies do not eliminate the stem cell component, which may be more resistant to chemotherapy. Precise human lung cancer stem cells have yet to be identified.

Lung cancer cells harbor multiple chromosomal abnormalities, including mutations, amplifications, insertions, deletions, and translocations. One of the earliest set of oncogenes found to be aberrant was the MYC family of transcription factors (MYC, MYCN, and MYCL). MYC is most frequently activated via gene amplification or transcriptional dysregulation in both SCLC and NSCLC, whereas abnormalities of MYCN and MYCL generally occur in SCLC. Currently, there are no MYC-specific drugs.

To date, among lung cancer histologies, adenocarcinomas have been the most extensively catalogued for recurrent genomic gains and losses as well as for somatic mutations. While multiple different kinds of aberrations have been found, a major class involves "driver mutations"—mutations that occur in genes encoding signaling proteins that when aberrant, drive initiation and maintenance of tumor cells (Table 35-2). Importantly, driver mutations can serve as Achilles' heels for tumors if their gene products can be targeted appropriately. For example, one set of mutations involves EGF-R, which belongs to the ERBB (HER) family of protooncogenes, including EGF-R (ERBB1), Her2/neu (ERBB2), HER3 (ERBB3), and HER4 (ERBB4). These genes encode cell-surface receptors consisting of an extracellular ligand-binding domain, a transmembrane structure, and an intracellular tyrosine kinase (TK) domain. The binding of ligand to receptor activates receptor dimerization and TK autophosphorylation, initiating a cascade of intracellular events, leading to increased cell proliferation, angiogenesis, metastasis, and a decrease in apoptosis. Lung adenocarcinomas can arise when tumors express mutant EGF-R. These same tumors display high sensitivity to small molecule EGF-R TK inhibitors. Additional examples of driver mutations in lung adenocarcinoma include those involving the signaling molecules downstream of EGF-R, e.g., the TK HER2; the GTPase, KRAS; the serine–threonine kinase, BRAF; and the lipid kinase, PIK3CA. In 2007, other subsets of lung adenocarcinoma were found to be defined by the presence of specific translocations fusing tyrosine kinases such as ALK and ROS to aberrant upstream partners. Notably, at least EGF-R, KRAS, and EML4-ALK mutations are mutually exclusive, suggesting that acquisition of one of these driver mutations is sufficient to promote tumorigenesis. Thus far, potentially targetable driver mutations have mostly been identified in lung adenocarcinomas as opposed to lung cancers displaying other types of histologies.

A large number of tumor-suppressor genes (recessive oncogenes) have also been identified that are inactivated during the pathogenesis of lung cancer (Table 35-2). Such genes include TP53, RB1, RASSF1A, CDKN2A/B, LKB1 (STK11), and FHIT. Nearly 90% of SCLCs harbor mutations in TP53 and RB1. Several tumor-suppressor genes on chromosome 3p appear to be involved in nearly all lung cancers. Allelic loss for this region occurs very early in lung cancer pathogenesis, including in histologically normal smoking-damaged lung epithelium.

The clinical outcome for lung cancer is related to the stage at diagnosis. Accordingly, it is presumed that early detection of occult tumors will lead to improved survival. Early detection is a process that involves screening tests, surveillance, diagnosis, and early treatment. By contrast, screening is defined as a systematic testing of asymptomatic individuals for preclinical disease. The majority of patients with lung cancer present with advanced disease, raising the question as to whether screening could detect lung tumors at earlier stages when they are theoretically more curable. In order for a screening program to be successful, the burden of disease within the population must be high, effective treatment must be available that can reduce mortality rate, and the test must be accessible, cost-effective, and both sensitive and specific. With any screening procedure, one must keep in mind the possible influence of lead-time bias (i.e., detecting the cancer earlier without an effect on survival), length time bias (i.e., indolent cancers are detected on screening and may actually not affect survival, while aggressive cancers are likely to cause symptoms earlier in patients and are less likely to be detected), and overdiagnosis (i.e., diagnosing cancers so slow growing that they are unlikely to cause the death of the patient) (Chap. 27).

Randomized controlled trials from the 1960s to the 1980s reported no impact on lung cancer–specific mortality rate using screening chest radiographs with or without sputum cytology in high-risk patients (age >50 years or history of smoking). Although these studies have been criticized for their design, statistical analyses, and outdated imaging modalities, they resulted in the current recommendations not to use these tools to screen for lung cancer. The more recent Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial has completed accrual. This study involved more than 150,000 patients randomized to standard care or a baseline single-view posterior-anterior chest radiograph. A total of 5991 (8.9%) baseline chest radiographs were reported as suspicious for lung cancer, highest in current and former smokers. A total of 206 patients had a biopsy, of which 126 (61%) were positive for lung cancer. Among those with positive biopsies, 52% were stage I, 12% were stage II, and 22% were stage III. Long-term follow-up is required to determine the effect on mortality rate, if any.

Low-dose, noncontrast, thin-slice helical or spiral chest CT has emerged as a possible new tool for lung cancer screening. In a spiral chest CT scan, only the pulmonary parenchyma is examined, thus negating the use of intravenous contrast and the necessity of a physician being present at the exam. The scan can usually be done quickly (within a breath) and involves low doses of radiation. However, the benefits of screening with such technology remain to be determined. The International Early Lung Cancer Action Project (I-ECLAP) screened 31,567 asymptomatic patients at high risk for lung cancer (age ≥60 years with history of at least a 10-pack-year smoking history) using low-dose baseline CT and annual screening in 27,456 study participants. Suspicious lesions requiring biopsies were indicated in 535 participants. Lung cancer was diagnosed in 484 participants–405 at baseline, 74 on subsequent screening, and 5 participants due to symptoms between annual visits. Of the 484 participants who received a diagnosis of lung cancer, 412 (85%) were clinical stage I with an estimated 10-year survival rate of 88% regardless of treatment and 92% among the 302 participants who underwent resection within 1 month after diagnosis. A second trial randomized 1276 patients to low-dose CT screening and 1196 to baseline chest radiography followed by yearly medical examination. At 3-year follow-up, this study found a trend toward more patients being diagnosed with stage I lung cancer in the low-dose CT arm, with no difference in the number of patients diagnosed with advanced lung cancer or lung cancer deaths. More mature data from all trials are required to determine whether screening reduces lung cancer mortality rates.

A major challenge confronting advocates of CT screening is the high false-positive rate; on initial screening of at-risk populations, false-positive rates range between 10 and 20% but can be as high as 50%, depending on the geographical region. Positive predictive values range from 2.8 to 11.6%. False-positive results can have a substantial impact on patients through the expense and risk of unneeded further evaluation and emotional stress. False-positive rates and positive predictive values are somewhat improved in annual follow-up CT scans, but there is still significant room for improvement. Based on extant data, it appears that nodules <0.5 mm are unlikely to be cancerous and those 5–10 mm in diameter (25–40% of noncalcified nodules detected) are of uncertain significance. The management of these patients usually consists of serial CT scans over time to see if the nodules grow, attempted fine-needle aspirates, or surgical resection (Fig. 35-3).

Two additional screening studies are ongoing, the National Lung Cancer Screening Trial (NLST), a prospective comparison of spiral CT and standard chest radiographs in 50,000 current or ex-smokers and a similar study in Europe comparing CT scanning with standard of care in subjects with a history of heavy smoking. Until these data and more mature data from the above-mentioned trials become available, routine CT screening for lung cancer cannot be recommended for any risk group. For patients who want to be screened, physicians need to discuss the possible benefits and risks of screening. While lung cancers may be found, patients are at risk for more radiation exposure and false-positive results. The latter can result in multiple follow-up CTs and possible invasive procedures, with potential added costs, anxiety, and morbidity and mortality rates. There are no data on screening never smokers for lung cancer.

More than half of all patients diagnosed with lung cancer present with advanced disease at the time of diagnosis. The majority of patients present with signs, symptoms, or laboratory abnormalities that can be attributed to the primary lesion, local tumor growth, invasion or obstruction of adjacent structures, growth at distant metastatic sites, or a paraneoplastic syndrome (Tables 35-3 and 35-4). The prototypical lung cancer patient is a current or former smoker of either sex, usually in the seventh decade of life. A history of chronic cough with or without hemoptysis in a current or former smoker with chronic obstructive pulmonary disease (COPD) age 40 years or older should prompt a thorough investigation for lung cancer even in the face of normal chest radiography findings. A persistent pneumonia without constitutional symptoms and unresponsive to repeated courses of antibiotics also should prompt an evaluation for the underlying cause.

Lung cancer arising in a lifetime never smoker is more common in women and East Asians. Such patients also tend to be younger than their smoking counterparts at the time of diagnosis. The clinical presentation of lung cancer in never smokers tends to mirror that of current and former smokers.

Patients with central or endobronchial growth of the primary tumor may present with cough, hemoptysis, wheeze, stridor, dyspnea, or postobstructive pneumonitis. Peripheral growth of the primary tumor may cause pain from pleural or chest wall involvement, dyspnea on a restrictive basis, and symptoms of a lung abscess resulting from tumor cavitation. Regional spread of tumor in the thorax (by contiguous growth or by metastasis to regional lymph nodes) may cause tracheal obstruction, esophageal compression with dysphagia, recurrent laryngeal paralysis with hoarseness, phrenic nerve palsy with elevation of the hemidiaphragm and dyspnea, and sympathetic nerve paralysis with Horner's syndrome (enophthalmos, ptosis, miosis, and anhidrosis). Malignant pleural effusions can cause pain or dyspnea. Pancoast (or superior sulcus tumor) syndromes result from local extension of a tumor growing in the apex of the lung with involvement of the eighth cervical and first and second thoracic nerves, with shoulder pain that characteristically radiates in the ulnar distribution of the arm, often with radiologic destruction of the first and second ribs. Often Horner's syndrome and Pancoast syndrome coexist. Other problems of regional spread include superior vena cava syndrome from vascular obstruction; pericardial and cardiac extension with resultant tamponade, arrhythmia, or cardiac failure; lymphatic obstruction with resultant pleural effusion; and lymphangitic spread through the lungs with hypoxemia and dyspnea. In addition, lung cancer can spread transbronchially, producing tumor growth along multiple alveolar surfaces with impairment of gas exchange, respiratory insufficiency, dyspnea, hypoxemia, and sputum production. Constitutional symptoms may include anorexia, weight loss, weakness, fever, and night sweats. Apart from the brevity of symptom duration, these parameters fail to clearly distinguish SCLC from NSCLC or even from neoplasms metastatic to lungs.

Extrathoracic metastatic disease is found at autopsy in >50% of patients with squamous carcinoma, 80% of patients with adenocarcinoma and large cell carcinoma, and >95% of patients with SCLC. Approximately one-third of patients present with symptoms as a result of distant metastases. Lung cancer metastases may occur in virtually every organ system, and the site of metastatic involvement largely determines other symptoms. Patients with brain metastases may present with headache, nausea and vomiting, or neurologic deficits. Patients with bone metastases may present with pain, pathologic fractures, or cord compression. The latter may also occur with epidural metastases. Individuals with bone marrow invasion may present with cytopenias or leukoerythroblastosis. Those with liver metastases may present with hepatomegaly, right upper quadrant pain, anorexia, and weight loss. Liver dysfunction or biliary obstructions are rare. Adrenal metastases are common but rarely cause pain or adrenal insufficiency unless they are large.

Paraneoplastic syndromes are common in patients with lung cancer, especially those with SCLC, and may be the presenting finding or the first sign of recurrence. In addition, paraneoplastic syndromes may mimic metastatic disease and, unless detected, lead to inappropriate palliative rather than curative treatment. Often the paraneoplastic syndrome may be relieved with successful treatment of the tumor. In some cases, the pathophysiology of the paraneoplastic syndrome is known, particularly when a hormone with biologic activity is secreted by a tumor. However, in many cases, the pathophysiology is not known. Systemic symptoms of anorexia, cachexia, weight loss (seen in 30% of patients), fever, and suppressed immunity are paraneoplastic syndromes of unknown etiology or at least not well defined. Weight loss greater than 10% of total body weight is considered a bad prognostic sign. Endocrine syndromes are seen in 12% of patients; hypercalcemia resulting from ectopic production of parathyroid hormone (PTH), or more commonly, PTH-related peptide, is the most common life-threatening metabolic complication of malignancy, primarily occurring with squamous cell carcinomas of the lung. Clinical symptoms include nausea, vomiting, abdominal pain, constipation, polyuria, thirst, and altered mental status.

Hyponatremia may be caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or possibly atrial natriuretic peptide (ANP). SIADH resolves within 1–4 weeks of initiating chemotherapy in the vast majority of cases. During this period, serum sodium can usually be managed and maintained above 128 meq/L via fluid restriction. Demeclocycline can be a useful adjunctive measure when fluid restriction alone is insufficient. Of note, patients with ectopic ANP may have worsening hyponatremia if sodium intake is not concomitantly increased. Accordingly, if hyponatremia fails to improve or worsens after 3–4 days of adequate fluid restriction, plasma levels of ANP should be measured to determine the causative syndrome.

Ectopic secretion of ACTH by SCLC and pulmonary carcinoids usually results in additional electrolyte disturbances, especially hypokalemia, rather than the changes in body habitus that occur in Cushing's syndrome from a pituitary adenoma. Treatment with standard medications, such as metyrapone and ketoconazole, is largely ineffective due to extremely high cortisol levels. The most effective strategy for management of Cushing's syndrome is effective treatment of the underlying SCLC. Bilateral adrenalectomy may be considered in extreme cases.

Skeletal–connective tissue syndromes include clubbing in 30% of cases (usually NSCLCs) and hypertrophic primary osteoarthropathy in 1–10% of cases (usually adenocarcinomas). Patients may develop periostitis, causing pain, tenderness, and swelling over the affected bones and a positive bone scan. Neurologic–myopathic syndromes are seen in only 1% of patients but are dramatic and include the myasthenic Eaton-Lambert syndrome and retinal blindness with SCLC, while peripheral neuropathies, subacute cerebellar degeneration, cortical degeneration, and polymyositis are seen with all lung cancer types. Many of these are caused by autoimmune responses such as the development of anti–voltage-gated calcium channel antibodies in Eaton-Lambert syndrome. Patients with this disorder present with proximal muscle weakness, usually in the lower extremities, occasional autonomic dysfunction, and rarely with cranial nerve symptoms or involvement of the bulbar or respiratory muscles. Depressed deep tendon reflexes are frequently present. In contrast to patients with myasthenia gravis, strength improves with serial effort. Some patients who respond to chemotherapy will have resolution of the neurologic abnormalities. Thus, chemotherapy is the initial treatment of choice. Paraneoplastic encephalomyelitis and sensory neuropathies, cerebellar degeneration, limbic encephalitis, and brainstem encephalitis occur in SCLC in association with a variety of antineuronal antibodies such as anti-Hu, anti-CRMP5, and ANNA-3. Paraneoplastic cerebellar degeneration may be associated with anti-Hu, anti-Yo, or P/Q calcium channel autoantibodies. Coagulation, thrombotic, or other hematologic manifestations occur in 1–8% of patients and include migratory venous thrombophlebitis (Trousseau's syndrome); nonbacterial thrombotic (marantic) endocarditis with arterial emboli; and disseminated intravascular coagulation with hemorrhage, anemia, granulocytosis, and leukoerythroblastosis. Thrombotic disease complicating cancer is usually a poor prognostic sign. Cutaneous manifestations such as dermatomyositis and acanthosis nigricans are uncommon (1%), as are the renal manifestations of nephrotic syndrome and glomerulonephritis (≤1%).

Tissue sampling is required to confirm a diagnosis in all patients with suspected lung cancer. Tumor tissue may be obtained via minimally invasive techniques such as bronchial or transbronchial biopsy during fiberoptic bronchoscopy, by fine-needle aspiration (FNA) or percutaneous biopsy using image guidance, or via endobronchial ultrasound (EBUS)–guided biopsy. Depending on the location, lymph node sampling may occur via transesophageal endoscopic ultrasound guide biopsy (EUS), EBUS, or blind biopsy. In patients with clinically palpable lymph nodes, an FNA may be obtained. In patients with suspected metastatic disease, a diagnosis may be confirmed by percutaneous biopsy of a soft tissue mass, lytic bone lesion, bone marrow, pleural, or liver lesion or an adequate cell block obtained from a malignant pleural effusion. In patients with a suspected malignant pleural effusion, if the initial thoracentesis findings are negative, a repeat thoracentesis is recommended. While the majority of pleural effusions are due to malignant disease, particularly if they are exudative or bloody, some may be parapneumonic. In this case, patients should be considered for possible curative treatment.

The diagnostic yield of any biopsy 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, small cell carcinomas, or endobronchial lesions, such as carcinoid tumors, are more readily diagnosed by bronchoscopic examination, while peripheral lesions such as adenocarcinomas and large cell carcinomas are more amenable to transthoracic FNA. Diagnostic accuracy for SCLC versus NSCLC for most specimens is excellent, with lesser accuracy for subtypes of NSCLC.

Bronchoscopic specimens include bronchial brush, bronchial wash, bronchioloalveolar 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 together with tissue biopsy, the yield increases to 85–90%. Like transbronchial FNA specimens, transthoracic FNA specimens are also very good, yielding diagnostic material in 70–95% of cases. Sensitivity is highest for larger lesions and peripheral tumors. In general, FNA specimens, whether transbronchial, transthoracic, or endoscopic ultrasound-guided, are superior to other specimen types. This is primarily due to the higher percentage of tumor cells with fewer confounding factors, such as obscuring inflammation and reactive nonneoplastic cells. For more accurate histologic classification, mutation analysis, or for investigational purposes, reasonable efforts (e.g., a core-needle biopsy) should be made to obtain more tissue than what is contained in a routine cytology specimen obtained by FNA.

Sputum cytology is inexpensive and noninvasive but has a lower yield than other specimen types due 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 small cell carcinoma histology. The specificity for sputum cytology averages close to 100%, although sensitivity is generally less than 70%. The accuracy of sputum cytology improves with increased numbers of specimens analyzed. Consequently, analysis of at least three sputum specimens is recommended.

Lung cancer staging consists of two parts: first, a determination of the location of the tumor and possible metastatic sites (anatomic staging), and second, an assessment of a patient's ability to withstand various antitumor treatments (physiologic staging). All patients with lung cancer should have a complete history and physical examination, with evaluation of all other medical problems, determination of performance status, and history of weight loss. The most significant dividing line is between patients who are candidates for surgical resection and those who are inoperable but will benefit from chemotherapy, radiation therapy, or both. Staging with regard to a patient's potential for surgical resection is principally applicable to NSCLC.

ANATOMIC STAGING OF PATIENTS WITH LUNG CANCER

The accurate staging of patients with NSCLC is essential for determining the appropriate treatment in patients with resectable disease and avoiding unnecessary surgical procedures in patients with advanced disease (Fig. 35-4). All patients with NSCLC should undergo initial radiographic imaging with CT scan, positron emission tomography (PET), or preferably CT-PET. PET scanning attempts to identify sites of malignancy based on glucose metabolism by measuring the uptake of fluorodeoxyglucose F18. Rapidly dividing cells, presumably in the lung tumors, will preferentially take up ¹⁸F-FDG and appear as a "hot spot." To date, PET has been mostly used for staging and detection of metastases in lung cancer and in the detection of nodules >15 mm in diameter. Combined ¹⁸F-FDG PET-CT imaging has been shown to improve the accuracy of staging in NSCLC compared to visual correlation of PET and CT or either study alone. CT-PET has been found to be superior in identifying pathologically enlarged mediastinal lymph nodes and extrathoracic metastases. A standardized uptake value (SUV) of >2.5 on PET is highly suspicious for malignancy. False-negative results can be seen in diabetes, in lesions <8 mm, in slow-growing tumors, and in concurrent infections such as tuberculosis. False-positive results can be seen in infections and granulomatous disease. Thus, PET should never be used alone to diagnose lung cancer, mediastinal involvement, or metastases. Confirmation with tissue biopsy is required. For brain metastases, MRI is the most effective method. MRI can also be useful in selected circumstances, such as for superior sulcus tumors, to rule out brachial plexus involvement but in general does not play a major role in NSCLC staging.

In patients with NSCLC, the following are major contraindications to potential curative resection: extrathoracic metastases; superior vena cava syndrome; vocal cord and, in most cases, phrenic nerve paralysis; malignant pleural effusion; cardiac tamponade; tumor within 2 cm of the carina (potentially curable with combined chemoradiotherapy); metastasis to the contralateral lung; metastases to supraclavicular lymph nodes; contralateral mediastinal node metastases (potentially curable with combined chemoradiotherapy); and involvement of the main pulmonary artery. When it will make a difference in treatment, abnormal scan findings require tissue confirmation of malignancy so that patients are not precluded from having potentially curative surgery.

The best predictor of metastatic disease remains a careful history and physical examination. If signs, symptoms, or findings from physical examination suggest the presence of malignancy, then sequential imaging starting with the most appropriate study should be performed. If the findings from the clinical evaluation are negative, then imaging studies beyond CT-PET are unnecessary, and the search for metastatic disease is complete. More controversial is how one should assess patients with known stage III disease. Because these patients are more likely to have asymptomatic occult metastatic disease, current guidelines recommend a more extensive imaging evaluation, including imaging of the brain with either CT scan or MRI. In patients in whom distant metastatic disease has been ruled out, lymph node status needs to be assessed via a combination of radiographic imaging and/or minimally invasive techniques such as those mentioned earlier and/or invasive techniques such as mediastinoscopy, mediastinotomy, thoracoscopy, and thoracotomy. About one-quarter to half of patients diagnosed with NSCLC have mediastinal lymph node metastases at the time of diagnosis. Lymph node sampling is recommended in all patients with enlarged nodes detected by CT or PET scan and in patients with large tumors or tumors occupying the inner third of the lung. The extent of mediastinal lymph node involvement is important in determining the appropriate treatment strategy: surgical resection followed by adjuvant chemotherapy versus combined chemoradiotherapy alone (see later discussion). A standard nomenclature for referring to the location of lymph nodes involved with lung cancer has evolved (Fig. 35-5).

There are limited data on the use of CT-PET in the staging of patients with SCLC (Fig. 35-6). Current staging recommendations include a CT scan of the chest and abdomen (because of the high frequency of hepatic and adrenal involvement), MRI of the brain (positive in 10% of asymptomatic patients), and radionuclide (bone) scan if symptoms or signs suggest disease involvement in these areas. Bone marrow biopsies and aspirations are rarely performed given the low incidence of isolated bone marrow metastases. Confirmation of metastatic disease, ipsilateral or contralateral lung nodules, or metastases beyond the mediastinum may be achieved by the same modalities recommended above for patients with NSCLC.

If a patient has signs or symptoms of spinal cord compression (pain, weakness, paralysis, urinary retention), a spinal CT or MRI scan and examination of the cerebrospinal fluid cytology should be performed. If metastases are evident on imaging, a neurosurgeon should be consulted for possible palliative surgical resection and/or a radiation oncologist should be consulted for palliative radiotherapy to the site of compression. If signs of symptoms of leptomeningitis develop at any time in a patient with lung cancer, an MRI of the brain and spinal cord should be performed as well as a spinal tap for detection of malignant cells. If the spinal tap findings are negative, a repeat spinal tap should be considered. There is currently no approved therapy for the treatment of leptomeningeal disease.

THE STAGING SYSTEM FOR NON–SMALL CELL LUNG CANCER

The TNM International Staging System provides useful prognostic information and is used to stage all patients with NSCLC. The various T (tumor size), N (regional node involvement), and M (presence or absence of distant metastasis) are combined to form different stage groups (Table 35-5). The former TNM staging system for lung cancer (sixth edition) was developed based on a relatively small database of patients from a single institution. In 1999, the International Association for the Study of Lung Cancer established the lung cancer staging project and collected data on more than 68,000 cases from 46 sources in more than 19 countries to develop the new TNM (seventh edition) staging system, which came into use in 2010. As seen in Tables 35-5 and 35-6, the major distinction between the sixth and seventh edition staging system is within the T classification; T1 tumors are divided into tumors ≤2 cm in size, as these patients were found to have a better prognosis compared with tumors >2 cm but ≤3 cm. T2 tumors are divided into those that are >3 cm but ≤5 cm and those that are >5 cm but ≤7 cm. T3 tumors are >7 cm. T4 tumors include those that have additional nodules in the same lobe or tumors that have a malignant pleural effusion. No changes have been made to the current classification of lymph node involvement (N). Patients with metastasis may be classified as M1a, malignant pleural or pericardial effusion, pleural nodules or nodules in the contralateral lung, or M1b distant metastasis (e.g., bone, liver, adrenal, or brain metastasis). Based on these data, approximately one-third of patients have localized disease that can be treated with curative attempt (surgery or radiotherapy), one-third have local or regional disease that may or may not be amenable to a curative attempt, and one-third have metastatic disease at the time of diagnosis.

THE STAGING SYSTEM FOR SMALL CELL LUNG CANCER

Small cell lung cancer has a distinct two-stage system. Patients with limited-stage disease (LD) have cancer that is confined to the ipsilateral hemithorax and can be encompassed within a tolerable radiation port. Thus, contralateral supraclavicular nodes, recurrent laryngeal nerve involvement, and superior vena caval obstruction can all be part of limited-stage disease. Patients with extensive-stage disease (ED) have overt metastatic disease by imaging or physical examination. Cardiac tamponade, malignant pleural effusion, and bilateral pulmonary parenchymal involvement generally qualify disease as extensive-stage because the involved organs cannot be encompassed safely or effectively within a single radiation therapy port. Sixty to 70% of patients are diagnosed with extensive disease at presentation.

PHYSIOLOGIC STAGING

Patients with lung cancer often have other comorbid conditions related to smoking, including cardiovascular disease and COPD. To improve their preoperative condition, correctable problems (e.g., anemia, electrolyte and fluid disorders, infections, cardiac disease, and arrhythmias) should be addressed, appropriate chest physical therapy instituted, and patients should be encouraged to stop smoking. Since it is not always possible to predict whether a lobectomy or pneumonectomy will be required until the time of operation, a conservative approach is to restrict surgical resection to patients who could potentially tolerate a pneumonectomy. Patients with an FEV₁ (forced expiratory volume in 1 s) of greater than 2 L or greater than 80% of predicted can tolerate a pneumonectomy, and those with an FEV₁ greater than 1.5 L have adequate reserve for a lobectomy. In patients with borderline lung function but a resectable tumor, cardiopulmonary exercise testing could be performed as part of the physiologic evaluation. This test allows an estimate of the maximal oxygen consumption (Vo₂max). A Vo₂max <15 mL/(kg.min) predicts for a higher risk of postoperative complications. Patients deemed unable to tolerate lobectomy or pneumonectomy from a pulmonary functional standpoint may be candidates for more limited resections, such as wedge or anatomic segmental resection, although such procedures are associated with significantly higher rates of local recurrence and a trend toward decreased overall survival. All patients should be assessed for cardiovascular risk using American College of Cardiology and American Heart Association guidelines. A myocardial infarction within the past 3 months is a contraindication to thoracic surgery because 20% of patients will die of reinfarction. An infarction in the past 6 months is a relative contraindication. Other major contraindications include uncontrolled arrhythmias, an FEV₁ of less than 1 L, CO₂ retention (resting PCO₂ >45 mm Hg), DL_CO (carbon monoxide diffusing capacity) <40%, and severe pulmonary hypertension.

Benign tumors account for about 5% of all lung cancers. About half are hamartomas; the lungs are the site of about 90% of all hamartomas. The other half are bronchial adenomas.

HAMARTOMAS

Lung hamartomas are usually peripheral lung masses composed of normal pulmonary tissue components such as smooth muscle and collagen. They are more common in men than in women and have a peak incidence in the 60s. They are often incidental radiographic findings as solitary nodules. They have a pathognomonic "popcorn" pattern of calcification in some cases; however, without such a finding, resection is necessary to rule out malignancy, especially in smokers.

BRONCHIAL ADENOMAS

These are centrally located slow-growing endobronchial lesions that are generally carcinoid tumors (≥80%; Chap. 49), adenocystic tumors (so called cylindromas, 10–15%), or mucoepidermoid tumors (2–3%). Mean age at presentation is 45 years (range 15–60 years). Patients often give a history of chronic cough, intermittent hemoptysis, or repeated episodes of airway obstruction with atelectasis or pneumonias with abscess formation due to endobronchial lesions obstructing the airway. They are usually visible at bronchoscopy but are highly vascular and may bleed profusely after a bronchoscopic biopsy. They are largely curable by surgical resection (local excision), but they may recur locally or become invasive and metastasize. Five-year survival after resection is 95% if the disease is localized. For bronchial adenomas that spread, the course of disease can become highly aggressive, such as SCLC, or somewhat slower, such as carcinoid tumors. Therapy is generally dictated by the pace of the disease.