Brian Arnold and Mara Antonoff
This chapter is a revision and update of that included in previous editions of the TSRA Review written by Mary Carolyn Vinson (2nd edition) and Daniela Molena (1st edition).
Lung cancer is the leading cause of cancer-related deaths among men and women. It accounts for 22% of all cancer deaths and 13% of all newly diagnosed cancer cases. The American Cancer Society estimated approximately 228,820 new cases of lung cancer (116,300 in men and 112,520 in women) and 135,720 deaths from lung cancer (72,500 in men and 63,220 in women) for 2020. Each year, more people die of lung cancer than of colon, breast, and prostate cancer combined. Overall, the chance that a man will develop lung cancer in his lifetime is about 1 in 15; for a woman, the risk is about 1 in 17.
Risk factors
Tobacco smoking is the most significant risk factor for lung cancer, accounting for as much as 85% of lung cancer deaths. The relative risk (RR) of lung cancer in smokers is dependent on the histology and pack-year smoking history. Smoking greatly increases this risk of small cell lung cancer (RR 1.94 and 52.5 for <19 pack-year smokers and >56 pack-year smokers, respectively) and squamous cell carcinoma (RR 1.70 and 23.9) but has a more modest effect on the risk of adenocarcinoma (RR 1.50 and 11.5). Since 2005, the rates of lung cancer in men and women have decreased across all age groups except women age 50-54, in whom the rate has slightly increased over this period. This trend is consistent across histologic subtypes and is not explained by smoking trends. Historically, women are younger at diagnosis, have a higher chance of being “never smokers,” have higher rates of adenocarcinoma histological type, and have improved survival rates for all stages at diagnosis. Cigars and pipe smoking are also significant risk factors, although this risk is reduced compared to cigarette smoking. Second-hand smoke exposure confers a two-fold increased risk. The damage of smoking to the lungs is partially reversible and a 30% to 50% reduction in cancer mortality risk has been reported after 10 years of smoking cessation. Several other environmental carcinogens have been identified (i.e., asbestos, radon, tar, soot, arsenic, chromium, nickel, and air pollution), but account for only 10-15% of lung cancers altogether. Moreover, cigarette smoking interacts synergistically with these substances to increase lung cancer risk. For example, cigarette use combined with asbestos exposure is associated with a 50-fold increased chance of developing lung cancer. Recent studies utilizing genetic mapping suggest that some families are at higher risk of developing lung cancer, and higher mortality rates have been reported in relatives of patients with lung cancer. Multiple possible heritable genes have been identified in small familial studies, but the exact mechanisms are still unknown.
Screening
Due to the unfavorable natural history of the disease, the high treatment costs, and poor outcomes despite aggressive multimodality treatment, screening for lung cancer has been investigated for decades. In 2011, landmark findings from the National Lung Screening Trial (NLST) were published in the New England Journal of Medicine. These findings demonstrated that low-dose helical CT scans were efficacious for lung cancer screening and could reduce lung cancer deaths up to 20-fold compared to standard chest x-ray.
Pathology
The vast majority of primary lung cancers are comprised of two major histologic categories: Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC).
NSCLC is the most frequently identified histologic type, accounting for 85% of primary lung cancers, and can be further divided into the subtypes adenocarcinoma, squamous cell, and large cell. Adenocarcinoma is the most common subtype of mono-differentiated lung cancer, representing 38% of cases, followed by squamous cell carcinoma at 20%. The previous histologic subtype known as bronchoalveolar carcinoma (BAC) has now been renamed adenocarcinoma-in-situ and is histologically free of pleural, stromal, or vascular invasion. SCLC accounts for about 14% of all pulmonary carcinomas. SCLC often arises in large central airways, frequently presents at advanced stages of disease, and carries a poor prognosis. SCLC lies on the spectrum of neuroendocrine tumors of the lung (along with large cell and carcinoid tumors), and it is the most aggressive of the neuroendocrine tumors. Large cell carcinoma is an intermediate grade neuroendocrine tumor usually located in the peripheral lung parenchyma. Microscopically, large cell cancers have a cell size at least three times that of small cell cancers. These tumors almost always occur in heavy smokers. Carcinoid tumors (typical and atypical) account for 1-2% of pulmonary carcinomas.
Clinical presentation
Unless diagnosed by screening or found incidentally on an imaging study performed for other reasons, most patients present with symptoms that lead to a diagnosis of lung cancer. Common symptoms include cough, dyspnea, and hemoptysis. Pneumonias and lung abscesses can result from a post-obstructive process from a proximal tumor compressing or invading a major bronchus. Many patients with increased disease burden also experience generalized symptoms such as weight loss, anorexia, and fatigue. Patients with advanced or metastatic disease may also complain of neurologic symptoms (brain metastases) or bone pain (bone metastases). Invasion of tumors into adjacent structures can lead to pain, nerve dysfunction, fistulae, venous obstruction, and effusions. Superior vena cava (SVC) syndrome can result from compression or obstruction of venous drainage by large, proximal upper lobe tumors. Paraneoplastic syndromes may also be seen in approximately 10% of patients, more commonly in association with small cell and squamous cell cancers. The most common paraneoplastic syndromes are hypercalcemia in squamous cell carcinoma and syndrome of inappropriate anti-diuretic hormone (SIADH) in small cell lung cancer.
Diagnosis and staging
History, physical exam, and CXR are the common starting points in the diagnostic work-up for suspected lung cancer, but CT scanning provides the most detailed imaging information needed for a new diagnosis of lung cancer. Previous radiographs and CT scans should be reviewed for comparison, if available. A variety of techniques can be used to obtain tissue for histologic confirmation of a mass or nodule found on imaging study (e.g., sputum cytology, percutaneous transthoracic biopsy, bronchoscopic biopsy, fine needle aspirate (FNA) using endobronchial ultrasound (EBUS), and FNA using esophageal ultrasound). Tissue diagnosis should be sought and confirmed by the easiest and safest method and should be tailored to the patient’s clinical and radiographic presentation. Endobronchial lesions are most often accessible via standard bronchoscopic biopsy, those that are adjacent to central airways may be best accessed by EBUS, and more peripheral lesions may be most readily sampled via transthoracic biopsy. PET-CT scanning is an important diagnostic component in both the diagnosis and staging of lung cancer.
After tissue diagnosis demonstrates cancer, staging the disease is critical to direct treatment and determine prognosis. Lung cancer is staged using the TNM classification, outlined in the 8th edition of the AJCC Staging Manual (Table 4-1). The 8th edition was adopted in January 2018. The major changes from the 7th edition staging classification relate to the T stage and M stage. Tumors are subdivided in 1 cm increments up to 5 cm. Tumors >5 cm and ≤7 cm are now classified as T3 (previously T2). Tumors >7 cm are now classified as T4 (previously T3). Tumors that invade the mainstem bronchus or cause atelectasis or obstructive pneumonitis are classified as T2 regardless of distance to the carina or whether they cause partial or total lung collapse. Tumors involving the diaphragm are T4. Tumors with a single extrathoracic metastasis (including nonregional lymph nodes) are now classified as M1b, whereas tumors with multiple extrathoracic metastases either at a single site or multiple sites are classified as M1c.
In order to properly stage a patient, the mediastinum must be evaluated for metastases. In the past, mediastinoscopy was by far the most common way to stage the mediastinum and is still regarded as the “gold standard”. However, less invasive options, most notably EBUS with transbronchial FNA, have emerged with studies showing similar sensitivity and specificity to mediastinoscopy. All patients with potentially resectable disease should undergo bronchoscopy in some form prior to surgical resection. If there is clinical suspicion of distant metastatic disease, or for central tumors, or tumors greater than T1, MRI of the brain and PET-CT scan should be performed, as the most common sites for metastases are the brain, bone, and adrenal glands. Pathologic staging can only be assessed after surgical resection.
Preoperative risk assessment
Preoperative assessment of a patient being considered for surgical resection of lung cancer should consider the clinical extent of tumor involvement and weigh the risk of untreated lung cancer with the perioperative risks of resection. Perioperative risks can be extrapolated from the patient’s comorbidities and the long- and short-term tolerability of pulmonary parenchymal loss.
A cardiopulmonary evaluation is an essential part of assessing perioperative risks. Spirometry remains the most commonly used preoperative test, allowing measurement of the FEV1 and DLCO. DLCO has been shown to have a better correlation with postoperative death compared to FEV1. It should be clearly noted that predicted postoperative FEV1 <40% and/or predicted postoperative DLCO <40% should be considered very high-risk for surgery, with consideration given to nonoperative treatment options.
Cardiopulmonary exercise testing (CPET) and determination of VO2max can also be performed to assess risk of perioperative complications. VO2max is the most specific predictor of postoperative pulmonary complications. Alternative exercise tests may be used to predict VO2max when formal CPET is not available, including stair climbing and the 6-minute walk test. In general, a patient who can climb 22 meters of stairs (approximately 6-7 flights) has a VO2max >15 mL/kg/min. Patients with preoperative VO2max >15 mL/kg/min are not considered to be at increased risk of pulmonary complications or death, while patients with VO2max <10 mL/kg/min have a very high risk for postoperative complications.
Table 4-1. International staging of lung cancer (Adapted from Detterbeck F. The eight edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg. 2018 Vol 155:1).
| TNM Descriptors | |
| T – Primary Tumor | |
| Tx | Primary tumor cannot be assessed, or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ (squamous or adenocarcinoma, including adenocarcinoma with pure lepidic pattern ≤ 3 cm |
| T1 | Tumor ≤3 cm surrounded by lung or visceral pleura, not invading more proximal than lobar bronchus |
| T1mi | Minimally invasive adenocarcinoma (≤3 cm in size and ≤5 mm invasion) |
| T1a | Tumor ≤1 cm |
| T1b | Tumor >1 cm but ≤2 cm |
| T1c | Tumor >2 cm but ≤3 cm |
| T2 | Tumor >3 cm but ≤5 cm, or tumor with any of the following features: Involvement of main bronchus (not carina)Invasion of visceral pleuraAtelectasis or obstructive pneumonitis extending to the hilum |
| T2a | Tumor >3 cm but ≤4 cm |
| T2b | Tumor >4 cm but ≤5 cm |
| T3 | Tumor >5 cm but ≤7 cm or tumor with any of the following features: Invasion of chest wall, phrenic nerve, parietal pleura, pericardiumSeparate tumor nodule(s) in the same lobe |
| T4 | Tumor >7 cm or tumor that invades diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe |
| N – Regional Lymph Nodes | |
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Metastasis in ipsilateral pulmonary or hilar |
| N2 | Metastasis in ipsilateral mediastinal or subcarinal nodes |
| N3 | Metastasis in contralateral mediastinal or hilar nodes, ipsilateral or contralateral scalene or supraclavicular nodes |
| M – Distant Metastasis | |
| cM0 | No distant metastasis |
| M1 | Distant metastasis |
| M1a | Separate tumor nodules in a contralateral lobe, tumor with pleural or pericardial nodules, or malignant pleural or pericardial effusion |
| M1b | Single extrathoracic metastasis |
| M1c | Multiple extrathoracic metastases (1 or >1 organ) |
| T/M Subcategory | N0 | N1 | N2 | N3 |
| T1a | IA1 | IIB | IIIA | IIIB |
| T1b | IA2 | IIB | IIIA | IIIB |
| T1c | IA3 | IIB | IIIA | IIIB |
| T2a | IB | IIB | IIIA | IIIB |
| T2b | IIA | IIB | IIIA | IIIB |
| T3 | IIB | IIIA | IIIB | IIIC |
| T4 | IIIA | IIIA | IIIB | IIIC |
| M1a | IVA | IVA | IVA | IVA |
| M1b | IVA | IVA | IVA | IVA |
| M1c | IVB | IVB | IVB | IVB |
Suggested Readings
- National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N Engl J Med. 2011;365(5):395-409.
- Beckles MA, Spiro SG, Colice GL, Rudd RM. Initial evaluation of the patient with lung cancer: symptoms, signs, laboratory tests, and paraneoplastic syndromes. Chest. 2003;123(1 Suppl):97S-104S.
- Detterbeck FC. The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg. 2018;155(1):356-359.
- Jemal A, Miller KD, Ma J, et al. Higher Lung Cancer Incidence in Young Women Than Young Men in the United States. N Engl J Med. 2018;378(21):1999-2009.
- Khuder SA. Effect of cigarette smoking on major histological types of lung cancer: a meta-analysis. Lung Cancer. 2001;31(2-3):139-48.
- Sehgal IS, Dhooria S, Aggarwal AN, Behera D, Agarwal R. Endosonography Versus Mediastinoscopy in Mediastinal Staging of Lung Cancer: Systematic Review and Meta-Analysis. Ann Thorac Surg. 2016;102(5):1747-1755.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
