Historical Highlights

Lung cancer, once considered rare at the beginning of the 20th century, became a frequently diagnosed disease by the mid-1930s. Oschner and Debakey attributed the increased incidence to the rise in smoking, a link that was later supported by the findings of a case-control study in 1939.¹ The surgical treatment of lung cancer has evolved over time. The first successful single-stage pneumonectomy was performed by Graham and Singer in 1933,² and the modern technique of ligating individual pulmonary vessels and suturing the bronchus was first described by Reinhoff in 1947.³

Lung cancer originates from epithelial cells. The two broad categories of lung cancer are nonsmall cell lung cancer (NSCLC), which constitutes about 80 percent of lung cancers, and small cell lung cancer (SCLC).

Nonsmall Cell Lung Cancer

Adenocarcinoma

Adenocarcinoma, the most common type of NSCLC, is a malignant epithelial tumor with glandular differentiation or mucin production. Adenocarcinomas are white, fleshy solid tumors that are usually located in the periphery of the lung and involve the pleura and chest wall in 15 percent of patients. There are five macroscopic growth patterns of adenocarcinoma; the most common pattern is peripheral tumor with desmoplastic fibrosis retracting the overlying pleura. Other patterns include central or endobronchial adenocarcinoma, diffuse pneumonia-like consolidation or papillary growth, diffuse pleural thickening or pseudomesotheliomatous carcinoma, and adenocarcinoma arising in the background of underlying fibrosis. There are four distinct histologic patterns or subtypes of adenocarcinoma. They are acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin production. It is uncommon to have an adenocarcinoma consisting entirely of one histologic pattern. Most tumors have mixed histology although one subtype is frequently dominant. Immunohistochemistry of adenocarcinoma reveals the expression of the epithelial markers cytokeratin 7 (CK7) and thyroid transcription factor-1 (TTF-1).⁴ As the name implies, TTF-1 is a protein that not only regulates transcription of genes specific for thyroid, but is also specific for lung. Patients with lung tumor that is positive for TTF-1 but negative for thyroglobulin, a protein produced exclusively by thyroid, confirm that the tumor arises from the lung.

Squamous Cell Carcinoma

Squamous cell carcinoma, which constitutes approximately 40 percent of NSCLC, is a malignant, typically cavitary tumor that arises centrally from bronchial epithelium. Squamous cell carcinomas are usually white or gray and grow laterally along the bronchial mucosa (“creeping type”) or downward (“penetrating type”). Squamous cell carcinomas tumors show keratinization, pearl formation, and/or intercellular bridges on histopathologic examination, and immunohistochemistry reveals keratin, carcinoembryonic antigen, and cytokeratin 5 and 6 expression.⁴

Large Cell Carcinoma

Large cell carcinoma, which constitutes about 9 percent of NSCLC, is a poorly differentiated epithelial tumor consisting of sheets or nests of large polygonal cells with vesicular nuclei and prominent nucleoli. Large cell carcinoma is usually diagnosed by excluding other tumor types during histopathologic examination. Most large cell carcinomas are located in the peripheral lung and invade the visceral pleura, chest wall, or adjacent structures.

Neuroendocrine Tumors

Neuroendocrine tumors range from indolent to aggressive. The four types of neuroendocrine tumors—typical carcinoid, atypical carcinoid, small cell lung cancer, and large cell neuroendocrine carcinoma—all exhibit organoid nesting, palisading, a trabecular pattern, and a rosette-like structure. The main criterion used to distinguish the different types of neuroendocrine tumor is the number of mitoses per 10 high-power fields of magnification. Typical carcinoid tumors have two mitoses or less and do not have necrosis, atypical carcinoid tumors have between 2 and 10 mitoses or evidence of necrosis, and small cell lung cancers and large cell neuroendocrine carcinomas have 11 or more. A constellation of features distinguishes small cell lung cancer and large cell neuroendocrine carcinoma. Large cell neuroendocrine carcinoma has cytologic features of NSCLC with large cell size, low nuclear-to-cytoplasmic ratio, vesicular chromatin, and frequent nucleoli. On the other hand, small cell carcinoma has scant cytoplasm and absent or faint nucleoli. Immunohistochemistry of neuroendocrine tumors reveals cytokeratin, chromogranin, synaptophysin, CD57, and CD56 expression.⁴

Other Tumors

Adenosquamous carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, epithelial–myoepithelial carcinoma, and sarcomatoid carcinoma compose about 2 percent of NSCLC.⁵

Small Cell Lung Cancer

Small cell lung cancer is an epithelial tumor that consists of small cells with scant cytoplasm, ill-defined borders, finely granular nuclear chromatin, and absent nucleoli. Small cell lung cancer is usually a hilar or perihilar mass with mediastinal lymphadenopathy. The tumors are typically white-tan, soft, friable masses with extensive necrosis. Immunohistochemistry of small cell lung cancer reveals TTF-1, CD56, chromogranin, and synaptophysin expression.

Development of lung cancer is considered as a series of genetic changes induced by environmental factors, which leads a normal cell to develop into a cancer. These genetic changes are mutations of the tumor oncogenes and tumor suppressors as well as the change in the tumor microenvironment that allows the tumor to grow and metastasize into other organs.

Oncogenes and Tumor Suppressors

The two most common types of NSCLC are adenocarcinoma and squamous cell carcinoma, both of which develop from normal epithelium into invasive cancer through a series of genetic mutations of tumor oncogenes and tumor suppressors. In adenocarcinoma, the first histologically noticeable change is the development of atypical adenomatous alveolar hyperplasia, which then develops into bronchoalveolar carcinoma and ultimately invasive adenocarcinoma. The genetic changes that have been associated with this progression include mutations of the Kirsten rat sarcoma (K-RAS) viral oncogene homolog and epithelial growth factor receptor (EGFR) oncogenes as well as the p53 and p16 tumor suppressor genes. K-RAS encodes a membrane-associated G protein that serves as a link between tyrosine kinase receptors at the membrane and cytoplasmic second messenger molecules. Mutated K-RAS, which is found in 10 to 30 percent of lung adenocarcinomas, constitutively activates guanosine triphosphatase, which causes tumor cells to proliferate.⁶ About 10 to 40 percent of adenocarcinomas with wild-type K-RAS have an EGFR mutation, which has been associated with women, nonsmokers, and patients with bronchoalveolar adenocarcinomas.⁶ Mutated EGFR binds such ligands as EGF or transforming growth factor alpha and activates tyrosine kinase-containing signaling pathways, leading to tumor cell proliferation.^7,8

The p53 and p16 tumor suppressor genes are also involved in adenocarcinoma development. The p53 encodes a transcription factor that mediates cell cycle arrest and cell death after DNA damage.⁹ When p53 is mutated, cell division is uninhibited, and cell death is not induced, thus allowing tumor cells to proliferate. In contrast to p53’s mechanism of action, the p16 tumor suppressor gene activates the retinoblastoma (Rb) gene to cause cell cycle arrest at the G₁/S boundary. The most common p16 mutation is a loss of heterozygosity that is found in about 50 percent of lung adenocarcinomas and allows tumor cells to proliferate without inhibition.

Similar multistage changes lead to invasive squamous cell carcinoma of the lung. The transition from normal epithelium to squamous hyperplasia is the first detectable histologic change of the squamous cell epithelium. The cells then develop into squamous metaplasia, dysplasia, carcinoma in situ, and ultimately invasive carcinoma. Oncogene and tumor suppressor mutations occur at each stage of development. As in adenocarcinoma, p53 mutations are common in squamous cell carcinoma with a mutation rate of 60 to 70 percent⁶; however, very few K-RAS mutations (<1%) and EGFR mutations (<1%) occur in squamous cell carcinoma.⁶

About 90 percent of small cell lung carcinomas have p53 and/or Rb mutations. The Rb gene, which is downstream of the p16 pathway, impacts cell cycle regulation, and mutation of Rb leads to tumor cell proliferation. The Myc oncogene, a nuclear phosphoprotein that regulates cell growth and tumorigenesis, is amplified in 30 percent of small cell lung carcinomas.⁴

Tumor Microenvironment

Invasive carcinomas alter their environment to enable their growth, survival, and metastasis by releasing certain factors such as vascular endothelial growth factor (VEGF), which signals for angiogenesis.¹⁰ Invasive carcinomas also recruit leukocytes such as T cells and macrophages to enable metastasis. It is a complex interplay between the tumor and the environment, which allows the cancer to grow and escape its primary site of origin.

Epidemiology

In 2009, nearly 220,000 people were diagnosed with lung cancer in the United States and over 159,000 people died of the disease.¹¹ The overall 5-year survival for all lung cancer patients is 16 percent. Survival depends heavily on the stage of the disease at diagnosis. The lifetime risk for developing lung cancer in the United States is 1 in 14.¹¹ In the United States, the population-attributable risk of developing lung cancer is 90 percent from smoking, 10 percent from radon, 9 to 15 percent from other occupational exposures, 1 to 2 percent from outdoor pollutants, and <1 percent from dietary factors.

Lung cancer is one of the leading causes of preventable death. Smoking has long been known to cause lung cancer. The number of years and the volume of cigarettes (packs per day) that a person smokes are directly related to the risk of that person developing lung cancer. Active cigarette smokers are 20 times as likely as nonsmokers to develop lung cancer. Quitting smoking reduces a smoker’s risk of developing lung cancer; however, this reduced risk never equalizes to that of a never-smoker. In never-smoker, 25 percent of lung cancers are due to secondhand smoke. Studies have shown that people regularly exposed to secondhand smoke have a 30 percent higher risk of developing lung cancer than people who have never been or are rarely exposed to secondhand smoke.¹²

The second leading cause of lung cancer is radon, the first occupational carcinogen associated with lung cancer. Other occupational hazards include arsenic, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, and asbestos. Both smoking and asbestos exposure are independent risk factors for lung cancer; combined, they act synergistically to further increase the risk of developing lung cancer.¹²

The pattern of lung cancer incidence in the United States over the years reflects cigarette use among men and women. The rapid rise in smoking prevalence first occurred in men and then a parallel rise was seen in women 30 years later. This same pattern has also been seen in lung cancer prevalence. The lung cancer incidence among men, although still much higher than that among women, has peaked and begun to decline; however, lung cancer incidences in women continue to rise.

Racial differences have also been identified. Currently, African American men are at the highest risk for lung cancer. Although African American women and white women have the same risk for developing lung cancer, African American men have a significantly higher risk than white men for unknown reasons. Latinos, Native Americans, and Asians/Pacific Islanders have a significantly lower risk of lung cancer than whites and African Americans. A family history of lung cancer also increases one’s risk of developing the disease. Some researchers have postulated that consuming fruits and vegetables has a protective effect against lung cancer.¹²

Screening

A randomized control trial performed by The National Lung Screening Trial Research Team showed that patients who had low-dose CT performed yearly for 3 years showed a 20% relative reduction in mortality from lung cancer compared with patients who underwent three annual screenings of chest radiography. The group enrolled 53,454 patients who were at high risk for developing lung cancer and followed them for 5 years. The study showed that patients who were between 55 and 74 years of age with at least 30 pack-years history of smoking, or if former smoker, quit within the previous 15 years, had benefits from CT screening.¹³ This study provides definitive data on the role of CT screening for lung cancer and it should be recommended for patients who are at high risk for developing lung cancer.

Clinical Presentation

Lung cancer patients are typically in the fifth to seventh decades of life. Patients with early-stage lung cancer have clinically silent tumors and they are a minority. Most patients present with symptoms due to advanced disease.

Pulmonary Symptoms

Cough is the most common presenting pulmonary symptom in lung cancer patients. Other pulmonary symptoms include dyspnea, hemoptysis, and sputum production. Tumors obstructing the airway may cause atelectasis, obstructive pneumonitis, and/or pneumonia. Tumor invasion into the bronchial artery or other major blood vessels can cause hemoptysis. Pleural effusion caused by the tumor may result in dyspnea.¹⁴

Nonpulmonary Symptoms

Like many other cancer patients, lung cancer patients sometimes present with weight loss, fatigue, malaise, and anorexia. Patients can also present with symptoms caused by the tumor invading adjacent structures. Focal chest pain suggests chest wall or spinal involvement from local invasion or bone pain stemming from metastatic disease. Direct invasion or nodal involvement may lead to superior vena cava syndrome or invasion of the recurrent laryngeal nerve resulting in hoarseness. Involvement of the superior cervical ganglion can cause Horner syndrome, which is characterized by unilateral facial anhidrosis, ptosis, and miosis. Shoulder and arm pain may occur if an apical tumor invades the brachial plexus.

Although lung cancers can metastasize to every part of the body, they most commonly metastasize to the brain and bones, causing a number of distinct symptoms. Lung cancer metastasis in the bone can cause bone pain and/or pathologic fractures. Metastatic lesion in the brain is seen in about 10 percent of patients with lung cancer and it can cause neurologic changes. Additional common sites of metastasis include residual lung, the liver, and the adrenal glands.

About 10 percent of NSCLC patients present with paraneoplastic syndrome. The most common sign associated with the paraneoplastic syndrome is clubbing. In addition, patients may manifest endocrine symptoms such as hypercalcemia, Cushing syndrome, syndrome of inappropriate antidiuretic hormone hypersecretion, carcinoid syndrome, hypercalcitoninemia, hyperglycemia, and hyperthyroidism.

(See Also Chapter 3)

Diagnostic Studies

Chest radiographs showing lung nodules should be compared with previous imaging studies to determine whether the nodule is new or has grown. Patients with new or growing nodules and patients for whom previous imaging studies are unavailable should undergo chest CT to determine whether the nodule has features indicative of malignancy. Features such as a noncalcified spiculated lesion are very concerning for malignancy. There are predictive scoring systems based on both radiologic and clinical features.¹⁵ If malignancy is suspected, diagnostic CT-guided fine-needle aspiration biopsy of the nodule should be performed. Endobronchial ultrasonography or magnetic navigation system can be used to guide fine-needle aspiration biopsy if CT guidance is not possible. If image-guided fine-needle aspiration biopsy is not possible or if the risk of malignancy, based on clinical and radiographic features, is very high then video-assisted thoracoscopic surgery (VATS) or open thoracotomy and biopsy can be done to obtain a definitive diagnosis.

Staging

The clinical staging is performed using different tests to obtain the most accurate tumor–node–metastasis (TNM) staging of the patient. The T or tumor size and extent can be determined best by the CT scan of the chest. Next, the M and N stages are determined using a positron emission tomography (PET)/CT to identify metastatic disease and determine mediastinal lymph node involvement. If patient has a high-stage tumor based on PET/CT or if the patient has any neurologic symptoms, magnetic resonance imaging of the brain is performed to evaluate the brain for evidence of metastatic disease. A PET/CT used for lung cancer staging is not ideally suited to detect metastatic lesions to the brain. If there are positive lymph nodes in the mediastinum based on the PET/CT or the patient has a very large or central primary tumor then endobronchial ultrasonography with transbronchial biopsy or mediastinoscopy is used to evaluate the mediastinum for metastatic disease.

Small Cell Lung Cancer

Small cell lung cancer has classically been staged as either limited or extensive disease. The limited disease is restricted to one hemithorax and may be accompanied by ipsilateral pleural effusion and/or regional metastases in the ipsilateral and contralateral hilar, mediastinal, or supraclavicular lymph nodes. All other small cell lung cancers are defined as extensive disease. The recent edition of the staging system does advocate that TNM staging should also be used in staging small cell lung cancer.

Nonsmall Cell Lung Cancer

The guidelines for the 7th edition of the NSCLC staging system were set forth by the International Association for the Study of Lung Cancer (IASLC).¹⁶ This TNM system (Table 9-1) provides information about the extent of the primary tumor, extent of metastatic disease in regional lymph nodes (Fig. 9-1), and absence or presence of distant metastasis. The system can be applied to both clinical (cTNM) and postresection histopathologic (pTNM) assessments of NSCLC.¹⁶

Stages IA and IB describe small tumors that have not metastasized to the lymph nodes or other organs. Stage IA disease includes T1a tumors <2 cm and T1b tumors 2 to 3 cm (Fig. 9-2). Stage IB disease includes T2a tumors 3 to 5 cm (Fig. 9-3). Stages IIA and IIB describe larger tumors without lymph node involvement and small tumors with ipsilateral hilar lymph node involvement. Stage IIA disease includes T1a, T1b, and T2a tumors with N1, ipsilateral hilar lymph node involvement (Fig. 9-4) as well as T2b tumors 5 to 7 cm. Stage IIB disease includes T2b tumors with N1 involvement and T3 tumors. T3 is defined by size (>7 cm) but also includes tumors that invade resectable structures (the chest wall, diaphragm, phrenic nerve, mediastinal pleura, and parietal pericardium) endobronchial tumors that are <2 cm from carina (but not involving the carina), obstructing tumors that cause atelectasis or pneumonitis of an entire lung, and satellite tumors in the same lobe (Fig. 9-5).

Stage IIIA describes a set of tumors that involve the ipsilateral mediastinal lymph nodes (N2 disease; Fig. 9-6), advanced tumors with hilar lymph node involvement, or T4 tumors. They are T1, T2, or T3 tumors with N2, ipsilateral mediastinal lymph node involvement, T3 or T4 tumors with N1 involvement. T4 describes very advanced tumors that invade structures that are difficult to resect (heart, great vessels, recurrent laryngeal nerve, esophagus, vertebral body, and carina) or that possess a satellite tumor in a different lobe but within the ipsilateral lung (Fig. 9-7).

Stage IIIB describes T4 tumors with N2 disease or any tumor with N3, contralateral mediastinal lymph node disease (Fig. 9-8). Finally, stage IV describes any tumor with metastatic disease to other organs including the contralateral lung or malignant effusions (pleural or pericardial) (Figs. 9-9 and 9-10).

Future of Staging

Despite the improvements in prognostication with the revised staging system, patients in each stage remain heterogeneous with respect to their individual outcome. For example, 20 to 30 percent of T1aN0M0 tumor still recurs despite their early stage. Clearly this is due to the inherent biology of the tumor, which is not reflected in an anatomical staging system. Kratz et al. have shown that the 14 gene signature can be used to determine prognosis in patients with small node-negative lung tumors.¹⁷ The study shows that the 14 gene signatures can show which subgroup of patients may have worse prognosis. This may eventually lead to the addition of “biologic” or B category to our TNM classification system in the future.

There are three modalities to treat lung cancer: surgery, radiotherapy, and chemotherapy. Conceptually radiotherapy and surgery are therapies directed at local and regional disease whereas chemotherapy can address regional and metastatic disease. For curative intent, surgery does provide better overall survival compared with radiation for local disease. Radiotherapy is still a curative option especially for patients who cannot tolerate lung resection secondary to reduced lung function or significant comorbidities. Radiotherapy can also be used for palliation of symptomatic metastatic disease especially the brain and the bone. Below are some general guidelines for specific clinical stages.

Stage I and II Nonsmall Cell Lung Cancer

Surgery is the recommended initial treatment for patients with stage I or II lung cancer (Table 9-2). If pathology reveals positive margins following lung cancer resection, and the patient cannot tolerate additional pulmonary resection, radiotherapy can be offered to reduce the rate of local recurrence. Radiotherapy is also advocated in patients with early-stage disease who cannot tolerate lung resection because of poor medical condition or poor pulmonary function. Adjuvant chemotherapy should be considered for patients with pathologic stage II lung cancer as it has been shown to improve disease-free survival.

Surgery

The main goals of lung cancer surgery in patients with stage I or II disease are to completely remove the tumor, all associated hilar and intrapulmonary lymph nodes, and at least sample the ipsilateral mediastinal lymph nodes. If the tumor is locally invasive to nearby structures, en bloc resection should be performed and the margins sampled using frozen section biopsy to ensure that all of the tumor is resected. Similarly, frozen section evaluation of the bronchial margin should be performed. If either margin is positive, then the appropriate resection should be performed until a negative margin is obtained. If a positive margin remains and the patient cannot tolerate a further resection, postoperative radiotherapy to the involved margin is warranted.

Two surgical issues must be addressed when treating patients with stage I or II lung cancer. The first issue concerns the volume of lung that should be removed with the tumor (lobectomy or sublobar resection). The Lung Cancer Study Group randomized stage I tumors to lobectomy versus a sublobar resection. Lobectomy provided significantly longer disease-free survival and a lower recurrence rate than sublobar resection. However, the survival advantage was unable to achieve a statistically significant difference. On the basis of these findings, lobectomy remains the standard surgical treatment for NSCLC.¹⁸ Improvements in imaging have allowed tumors to be identified at an even smaller size prompting many investigators to reexamine this question. Retrospective studies have shown that sublobar resection offers good overall survival for the very small (T1a) tumors. This has prompted a new randomized multi-institutional trial initiated by the Cancer and Leukemia Group B (CALGB 140503) to investigate the disease-free survival in patients with NSCLC less than or equal to 2 cm who undergo sublobar resection versus lobectomy.

The second issue concerns the value of extended mediastinal nodal dissections. Specifically, does the addition of a complete nodal dissection in a patient with no evidence of mediastinal nodal involvement confer any survival benefit? The American College of Surgeons Oncology Group (ACOSOG Z0030) trial investigated whether mediastinal lymph node dissection provided any benefit in lung cancer patients with T1 or T2 tumors, N0 or N1 disease, and no evidence of N2 disease based on intraoperative nodal sampling (1 to 2 nodes removed from each accessible nodal station) at the time of thoracotomy. Their initial findings revealed no increased risk associated with the addition of a complete nodal resection.¹⁹ However, subsequent findings revealed no difference in local and regional recurrence rates or survival between patients who received lymph node sampling and patients who received full mediastinal lymph node dissection.²⁰ Although the trial did not address the role of mediastinal lymph node dissection in patients with N2 disease, it did suggest that mediastinal lymph node sampling may be appropriate in patients with early-stage lung cancer.