What every physician needs to know:
Lung cancer is the most common cause of cancer mortality worldwide. In the United States in 2015, there were an estimated 221,200 new cases of lung cancer and 158,040 deaths from the disease. Bronchogenic carcinoma, the most common type, refers to malignancies that originate in the lung parenchyma, trachea, and bronchi. Bronchogenic carcinoma can be divided into two main types: small cell carcinoma and non-small cell carcinoma.
The initial presentation of lung cancer cases varies. The process often begins when a patient presents to his or her primary care provider with signs and symptoms of disease. Alternatively, a lung nodule may be found as an incidental finding during an evaluation for other diseases or as part of a lung cancer screening program.
The initial evaluation should include a careful history and physical, including assessment of risk factors for lung cancer, prior history of cancer, and evaluation for evidence of distant metastases. The evaluation should also include a careful evaluation any concurrent pulmonary diseases, and assessments of comorbidities, functional status, and overall health status. Initially a chest x-ray may be useful, but most patients require additional imaging. CXR is less sensitive than CT scan, and a negative CXR does not rule out lung cancer. Additional imaging with CT or integrated CT-PET is warranted once a lung nodule or mass is identified.
The key goals of the initial diagnostic evaluation are to evaluate the patient’s underlying pulmonary physiology and ability to tolerate treatment; to Identify and characterize the target lesion(s) in order to assess the extent of disease, including disease within the lung, the mediastinal and hilar lymph nodes, and distant metastases; and to identify a target lesion for biopsy.
The target lesion chosen should be able to establish proof of the highest stage of disease, contingent upon accessibility and the risk involved with the procedures. Consideration of TNM staging is vital since biopsy of a lower-stage target will often result in additional procedures being required later to stage the patient more precisely. These unnecessary procedures can be avoided by careful imaging and planning.
For didactic and discussion purposes, it can be useful to talk about diagnosis and staging separately. However, good clinical practice integrates staging and diagnosis into a single unified process, so prior to doing a biopsy for diagnosis, the clinician must consider staging and the potential for treatment. Therefore, the initial workup includes assessments of pulmonary physiology and comorbidities, which are done in parallel with the initial imaging.
Lung tumors can be divided into primary lung tumors and pulmonary metastases. Primary lung tumors include bronchogenic carcinomas, other malignant primary lung tumors, and benign lung tumors. Bronchogenic carcinomas are further divided into non-small-cell lung cancers (NSCLC) and small-cell lung cancers. NSCLC accounts for about 80% of all lung cancers, small-cell lung cancers account for about 15%, other malignant primary tumors for about 4%, and benign lung tumors for about 1%.
The most common cancers that cause pulmonary metastases are breast, colorectal, renal cell, uterine leiomyosarcoma, and head and neck squamous cell carcinoma. Patients usually present with multiple peripheral pulmonary nodules or masses. Occasionally, solitary metastases are identified.
In terms of diagnosis, bronchoscopy or CT-guided fine-needle aspiration is usually best, but the best test depends on local expertise and the size and location of the lesions. Bronchoscopy is better for larger, central lesions, while smaller, more peripheral lesions are best approached with CT-guided FNA. Treatment of pulmonary metastases depends on the primary tumor type. In some situations, resection of isolated metastases (pulmonary metastasectomy) may be warranted.
Pulmonary metastasectomy in patients with good performance status is reasonable when other treatment options are not available. In general, patients should have controllable primary disease, no evidence of other extrathoracic disease, and sufficient cardiopulmonary reserve to tolerate resection. Patients who have colorectal carcinoma with metastases limited to the lung and liver are an exception to this rule and may in some cases benefit from combined hepatic and lung metastasectomy.
If the patient has a colorectal primary cancer as the source of lung metastases, the presence of mediastinal lymph node metastases contraindicate metastasectomy. Therefore, mediastinal lymph node evaluation prior to resection, either with endobronchial ultrasound-guided transbronchial needle or mediastinal lymph node dissection, is warranted for these patients. If the patient has a renal cell or sarcoma primary tumor, routine mediastinal lymph node evaluation is not warranted, since limited evidence suggests that survival may still be prolonged. For other types of tumors, the role of mediastinal lymph node evaluation prior to metastasectomy is unknown.
Are you sure your patient has lung cancer? What should you expect to find?
Signs and symptoms of lung cancer arise from local effects of the tumor on the lung and from distant effects that are due to metastatic disease and to paraneoplastic syndromes. The key symptoms and signs of lung cancer include cough; hemoptysis; dyspnea; chest pain; weight loss; hoarseness; extrapulmonary manifestations that are due to metastases; and paraneoplastic syndromes, including hypercalcemia, Cushing’s syndrome, neurologic paraneoplastic syndromes, and dermatomyositis/polymyositis.
The most common sites of symptomatic metastatic disease are the bones and the brain; liver and adrenal involvement is common but is rarely symptomatic early on.
Neurologic paraneoplastic syndromes associated with lung cancer
There is a wide variety of neurologic paraneoplastic syndromes associated with lung cancer. These neurologic manifestations can be the first presenting symptoms related to the lung cancer. A CT of the chest is warranted in current or former smokers who present with one of these symptoms. Of the different forms of lung cancer, small-cell carcinoma is the one most often associated with neurologic paraneoplastic syndromes.
Among the neurologic paraneoplastic syndromes seen with lung cancer, the most common are Eaton-Lambert Syndrome, cerebellar ataxia, encephalomyelitis, limbic encephalitis, sensory and autonomic neuropathies, and retinopathy. Most are immune-mediated, and autoantibodies can be identified in some cases. However, immunosuppression is generally not effective in controlling the paraneoplastic syndromes associated with lung cancer. Rather, treatment of the underlying malignancy should be the goal since the paraneoplastic syndrome symptoms will often resolve if the tumor responds.
Of the different forms of lung cancer, small-cell carcinoma is most frequently associated with Cushing’s syndrome. In this case, Cushing’s syndrome is caused by ectopic adrenal corticotropin hormone (ACTH). Signs and symptoms to look for include weight loss, hypertension, weakness, osteoporosis, and hirsutism. Laboratory abnormalities include hyperglycemia and hypokalemic metabolic alkalosis.
Of the different forms of lung cancer, SIADH is most often associated with small-cell lung cancer. Overall, about 10% of patients with small-cell lung cancer will demonstrate some degree of SIADH. SIADH results in hyponatremia, which initially causes symptoms of nausea, vomiting, and anorexia. When the hyponatremia occurs rapidly, cerebral edema may occur, manifesting as personality changes, confusion, coma, seizures, and even respiratory arrest. Treatment is based on the patient’s volume status: If the patient is hypovolemic, normal saline infusion is often sufficient; in patients that are euvolemic, fluid restriction alone may be sufficient. If necessary, demeclocycline or a vasopressin receptor antagonist can be used. In severe acute cases, 3% hypertonic saline may be warranted.
If hypertonic saline is used, the goal should be for a correction of 1-2 mmol per liter per hour, with a maximum of 10 mmol per liter per twenty-four-hour period.
Hoarseness is usually caused by recurrent laryngeal nerve involvement. The recurrent laryngeal nerve loops under the aortic arch on the left side. CT evaluation will frequently demonstrate tumor in this area. In smokers, an important consideration in the differential diagnosis of persistent hoarseness is primary laryngeal cancer. If there is no evidence of AP-window involvement in a lung cancer patient with persistent hoarseness, a complete evaluation of the pharynx and larynx, including either direct or indirect laryngoscopy with a digital scope, is warranted.
Hypercalcemia in patients with lung cancer arises either from metastatic disease to the bone or as part of a paraneoplastic syndrome. Patients with hypercalcemia should have a bone scan or PET scan to assess for metastatic involvement of the bones. The paraneoplastic syndrome is characterized by secretion of a parathyroid hormone-related protein, calcitriol, osteoclast activating factor, or other cytokines.
Hypercalcemia is more common in patients with squamous cell carcinoma than other forms of bronchogenic carcinoma. Signs and symptoms that should prompt consideration of hypercalcemia include nausea, vomiting, lethargy, polyuria, polydipsia, dehydration, and constipation. Late manifestations include confusion, delirium, and even coma. Left untreated, hypercalcemia can lead to renal failure and nephrocalcinosis. Patients with a serum calcium of 12 mg/dL or greater require treatment with hydration and bisphosphonates.
Beware: there are other diseases that can mimic lung cancer
Numerous benign lesions can simulate the radiologic appearance of lung cancer. These conditions include acute and chronic pneumonias, fungal infections, sarcoidosis, and congenital abnormalities like lung sequestration.
How and/or why did the patient develop lung cancer?
Risk factors for bronchogenic carcinoma include cigarette smoking, age, COPD, second-hand smoke exposure, prior radiation therapy, asbestos exposure, radon exposure, polycyclic aromatic hydrocarbon exposure, HIV, dietary supplementation with beta-carotene, pulmonary fibrosis/usual interstitial pneumonia (UIP), nickel exposure, and arsenic exposure.
Asbestos and lung cancer
Occupational exposure to asbestos increases the risk of bronchogenic carcinoma, and the risk is multiplied with smoking. Risk estimates vary, but in non-smokers with occupational exposure, the risk of lung cancer is increased to approximately six times that of non-exposed individuals. Smokers without asbestos exposure have an increased risk of eleven times that of non-smokers without exposure. Those with both asbestos exposure and a smoking history had an increased risk of up to 66 times that of those without any risk factors. Lung cancer is more common with exposure to amphibole than with exposure to chrysotile fibers. Asbestos is also the main risk factor for mesothelioma.
Cigarette smoking and lung cancer
It is estimated that 90% of lung cancers are smoking-related. The lifetime risk of cancer among non-smokers is estimated at 1% or less, while the cumulative incidence proportion of lung cancer among heavy smokers is about thirty times higher than that of nonsmokers. Risk of bronchogenic carcinoma is associated with the number of cigarettes smoked per day, duration of smoking, degree of inhalation, age at onset, use of filters, and tar and nicotine content.
While most patients start smoking in their teens and early twenties, the impact of smoking on lung cancer risk is usually delayed, with the relative risk of lung cancer in smokers, as compared to non-smokers, starting to increase when patients are in their forties.
Similarly, smoking cessation decreases the risk of lung cancer, but an increased risk for cancer may persist in ex-smokers for several decades after smoking cessation.
Which individuals are of greatest risk of developing lung cancer?
Smoking cigarettes creates the greatest risk for lung cancer, with the addition of risk factors like asbestos exposure increasing the risk.
What Laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
Routine studies to obtain initially include:
CT scan of the chest with contrast, with the goal of using imaging to identify the size, location, and extent of disease
CT-PET in most cases will be warranted if the lesion is 8-10 mm or larger.
Routine liver function tests
Pulmonary Function Tests including DLCO
Additional imaging studies of other areas, if warranted
Additional imaging studies of other areas of the body are warranted if the history, physical, or laboratory studies suggest evidence of metastatic disease to a particular area. Specifically, if there are central nervous system abnormalities, either a contrast enhanced CT of the brain or contrast enhanced MRI is warranted. For detection of most other sites of metastatic disease, PET is sufficient.
What imaging studies will be helpful in making or excluding the diagnosis of lung cancer?
The main chest imaging studies used for lung cancer are chest x-rays, chest CT scans, and PET scans. A chest x-ray is usually obtained when patients first present with signs and symptoms suspicious of lung cancer. However, chest x-rays may fail to detect smaller tumors or centrally located tumors. Therefore, in patients with suspected lung cancer and suspicious symptoms, there should be a low threshold to obtain a contrast-enhanced CT of the chest. The CT will be useful for most patients in which bronchogenic carcinoma is suspected, since it will help identify distant metastases and mediastinal lymph node involvement simultaneously.
Clinicians should pay particular attention to the size, location, and number of lesions and to the presence of lymphadenopathy.
Lesions less than or equal to 3 cm in long-axis diameter on CT are classified as pulmonary nodules, and those larger than 3 cm are pulmonary masses. Masses greater than 3 cm have a 90% or greater probability of being malignant.
Location of the lesion(s) relative to other vital structures in the chest, such as the mediastinum, pleura, great vessels, heart, and trachea, impacts staging and treatment if the lesion is an NSCLC, in which case CT imaging is usually best. MRI imaging of the chest is generally not useful except when there is a suspicion of chest wall invasion, mediastinal invasion, or spinal cord invasion.
Multiple nodules suggest either metastatic disease to the lung or more advanced lung cancer. If the diagnosis is NSCLC, then the number of lesions and their location impact the stage.
Normal lymph nodes are less than 1 cm in short axis diameter on CT. Patients with enlarged hilar or mediastinal lymph nodes warrant additional mediastinal lymph node sampling.
What are the role and performance characteristics of chest CT for lung cancer?
CT of the chest should be performed with contrast if there are no contraindications, since contrast improves the ability of CT to distinguish vascular from mediastinal structures. For lung cancer evaluations, a chest CT should image from the base of the neck to below the adrenals. For peripheral nodules and masses, CT offers the benefit of facilitating densitometry measurement, which can be useful for detecting calcification (usually associated with a benign etiology, depending upon the pattern) or fat density (suggesting hamartoma).
For peripheral nodules, border characteristics can be used to risk-stratify nodules with respect to the probability of cancer. Nodules with irregular, lobulated, or spiculated borders are associated with a higher probability of cancer than lesions with a smooth border.
Lesions with a pure ground-glass or semi-solid appearance have a higher probability of cancer than do solid lesions of equivalent size.
CT also facilitates coronal and sagittal reconstructions and is better than chest x-ray at detecting mediastinal and chest wall invasion.
In addition, CT facilitates visualization and measurement of mediastinal and hilar lymph nodes. Using a threshold of 1 cm in short-axis diameter to define lymph node enlargement, a meta-analysis determined the sensitivity of CT in detecting malignant lymph node involvement to be 51% and the specificity to be 86%. The key point is that lymph node enlargement on CT, while increasing the probability of malignant nodal disease, is not sufficient to prove it. Therefore, tissue sampling, usually with endobronchial ultrasound or mediastinoscopy, is needed if there is evidence of lymph node enlargement on CT.
What patterns of calcification are associated with benign lung nodules and which ones are more likely to be malignant?
When calcifications are seen in a pulmonary nodule, they often indicate a benign diagnosis. However, not all patterns of calcification are benign. Diffuse, central, and laminated patterns of calcification usually indicate a benign disease, while a popcorn pattern is often indicative of a hamartoma. Fat density is a more sensitive indicator than a popcorn pattern for hamartoma. If only these patterns are present in a solitary pulmonary nodule, then no additional evaluation is usually necessary. However, stippled or eccentric patterns do not exclude malignancy, so they warrant further evaluation.
What are the role and performance characteristics of positron emission tomography (PET)?
PET measures metabolic activity by assessing 18-fluoro-2-deoxyglucose (FDG) uptake. Malignant cells tend be more metabolically active than benign cells are and to take up more FDG, resulting in a positive PET scan in that area. As such, PET provides information about relative tissue metabolism, rather than about anatomy, and it is useful in determining whether or not a lesion is likely to be malignant.
Today, most PET scans are integrated with CT-PET images, so metabolic and anatomic information is provided concurrently.
PET can be used to distinguish benign from malignant nodules or masses, to assess mediastinal lymph nodes, and to look for distant metastases. When applied to the problem of distinguishing benign from malignant pulmonary nodules and masses, PET has a sensitivity of 87% and a specificity of 83%. The sensitivity of PET drops if the lesion is less than 8 mm in size. False negatives are known to occur with PET, particularly in patients with bronchioloalveolar carcinoma, carcinoid tumors, and mucinous adenocarcinomas.
False positives are associated with inflammatory conditions like sarcoidosis and rheumatoid nodules; other causes of false positive PET scans include infectious processes like endemic mycoses and mycobacterial infections.
When applied to the problem of distinguishing benign from malignant mediastinal lymph node involvement, PET, with a sensitivity of 74% and a specificity of 85%, is more sensitive and more specific than CT. While PET has good negative predictive value, a positive PET scan does not have a sufficiently high positive predictive value to eliminate surgery as an option. Therefore, patients whose PET scans are positive for mediastinal lymph nodes should undergo additional tissue sampling, usually with EBUS or mediastinoscopy.
When applied to detection of extrathoracic metastatic disease, PET is generally superior to CT, and integrated PET/CT is superior to either PET alone or CT alone. The sensitivity, specificity, positive predictive value, and negative predictive value of integrated PET/CT for extrathoracic disease detection are about 98%, 92%, 89% and 98%, respectively. However, caution is warranted, since false positives do occur. In particular, if only one possible solitary metastasis is identified by PET, then there is about a 46% chance that the metastasis is not the only ones. In such cases, tissue sampling of the metastatic area is warranted.
The only area in which PET is not superior to CT in detecting extrathoracic metastasis is the brain because of the high glucose uptake of the surrounding tissue. Therefore, patients with neurologic symptoms in whom metastatic disease to the CNS is suspected and patients with a high pretest probability of CNS disease, should undergo dedicated imaging with either MRI or contrast-enhanced CT.
NSCLC and multiple nodules
A T3 case occurs when there are separate nodules in the same lobe, and a T4 case occurs if there are separate nodules in different lobes of the same lung. Distant metastatic disease (M1a) occurs if there are separate nodules in both lungs. The stage of NSCLC dictates treatment, so each of these cases could be treated differently.
Location of NSCLC and the TNM system
The location of the tumor affects the T stage. Tumors that involve the main bronchi and that are two or more cm away from the main carina, that involve only the visceral pleura, or that are associated with atelectasis of one lobe of the lung or less are T2 tumors.
Tumors that involve the main bronchi within 2 cm of the main carina but that have no carinal involvement, and those with involvement of the chest wall, diaphragm, parietal pericardial, mediastinal pleural, or phrenic nerve or that feature atelectasis of the entire lung are T3 tumors. Tumors that involve vital structures like the main carina, trachea, heart, great vessels, esophagus, recurrent laryngeal nerve, or vertebral bodies through direct extension are T4 tumors.
What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of lung cancer?
The goal of pulmonary function tests is to define the patient’s pulmonary physiology. Patients with limited cardiopulmonary reserve may not be candidates for surgical resection, and this may also affect the optimal diagnostic approach.
What diagnostic procedures will be helpful in making or excluding the diagnosis of lung cancer?
Useful diagnostic procedures include CT-guided fine-needle biopsy, bronchoscopy, thoracentesis, and sputum cytology, as well as video-assisted thorascopic or open surgical biopsy (wedge), followed by resection when indicated.
CT-guided fine-needle biopsy: Sensitivity is 65-94% with a median of 90%. Pneumothorax rate is 15-43% with a median of 27%; only 4-18% require chest tubes.
Bronchoscopy: Sensitivity is best for centrally located and larger lesions. For central endobronchial lesions, sensitivity is 88%. The diagnostic yield decreases for peripheral lesions and for smaller lesions. If the lesion is peripheral and larger than 2 cm, sensitivity is 63%. For peripheral lesions smaller than 2 cm, sensitivity is 34% or less. Advanced bronchoscopic techniques, such as radial endobronchial ultrasound and electromagnetic navigation, may improve the diagnostic yield in some cases.
Thoracentesis: Thoracentesis is useful in patients who present with pleural effusions. The sensitivity of three thoracenteses for patients with malignant effusions is approximately 80-90%. If repeat thoracentesis is non-diagnostic, thoracoscopy is warranted to rule out pleural involvement.
Sputum cytology: Sensitivity varies by location of the tumor, but it tends to be higher for central endobronchial lesions and lower for peripheral lesions. Pooled sensitivity is about 66%, but there is significant variation between labs, and sensitivity varies with sputum induction.
Biopsy of distant metastases: If distant metastases are evident, such as to the liver, it is often best to consider biopsy of these distant sites first in order to establish the diagnosis and effectively stage the patient (i.e., identify that the patient has distant metastases).
The complex choice of which test is best for a given patient is covered under diagnostic strategy for lung cancer.
Diagnostic strategy for lung cancer
In general, for patients with suspected primary lung cancer, biopsying the site of disease that will confirm the highest stage is the best approach since it will minimize the total number of biopsies required.
If there are potential metastases after an initial history and physical, PFTs, and PET scan, it is often best to start with a biopsy of a metastasis in order to acquire diagnostic and staging information sufficient to guide treatment. In some instances, there may be overwhelming evidence from imaging of distant metastasis (e.g., multiple bone metastases or multiple brain metastases), in which case it is reasonable to establish a tissue diagnosis by biopsying the most accessible site that involves the least risk relative to diagnostic yield.
If there is no evidence of distant metastatic disease after the initial history and imaging workup, an evaluation of the mediastinum is warranted. If there are any enlarged mediastinal or hilar lymph nodes by CT, if any of the lymph nodes are metabolically active on PET, or if the primary tumor is centrally located, bronchoscopy with EBUS-guided TBNA of the lymph nodes is warranted.
This choice is better than CT-guided fine-needle biopsy because it will both establish a diagnosis and stage the patient. During the EBUS-guided TBNA procedure, biopsy of the peripheral mass can be performed as well in case the lymph nodes are negative for malignancy.
If there is no evidence of distant metastatic disease after the initial history and imaging workup and there is no evidence of mediastinal lymph node disease by CT or PET, then the evaluation depends on the size of the lesion. With lesions that are larger than 3 cm, the probability of lung cancer is greater than 90%, so the lesion should be considered malignant until proven otherwise. If the lesion is peripheral and is located near the pleura, CT-guided FNA will have the highest diagnostic yield.
Alternatively, if the lesion is central or has an air-bronchogram, then bronchoscopy should be performed when the pretest probability of malignancy is high and the lesion is not accessible to CT-guided FNA. When biopsies have been non-diagnostic, proceeding directly to video-assisted thoracoscopic biopsy may be warranted; a wedge biopsy with frozen section should be done. If non-small-cell lung cancer is identified, a full lymph node dissection is needed. A lobectomy is a good alternative in select patients who are good surgical candidates.
As for lesions that are smaller than or equal to 3 cm, the probability of lung cancer varies depending on clinical risk factors and the size of the lesion. These lesions are classically termed solitary pulmonary nodules. Their management, which is complex, is covered separately.
Pulmonary nodule evaluation and management
Pulmonary nodules are, by definition, 3 cm or less in size. The main management options include careful observation, diagnostic testing, or proceeding to surgical biopsy and resection. Proper management requires consideration of the pretest probability of cancer and an assessment of the patient’s surgical risk. The pretest probability of cancer is determined by considering the risk factors, such as size of the lesion, smoking history, age, location of the lesion, history of other cancers, and CT characteristics.
In patients whose pretest probability of cancer is less than 10%, a strategy of careful observation with serial CT imaging is reasonable.
A diagnostic test is usually warranted for patients with an intermediate probability of cancer (10-60%). The two main test options are PET scan and CT-guided FNA. (PET is useful for nodules 8 mm or larger.) If both CT and PET are negative, then a careful observation strategy can be followed. If either is positive, then surgery is warranted.
Video-assisted thoracoscopic biopsy and resection is reasonable for patients who have a high probability of cancer (>60%).
Patient preferences and risk tolerance are important to elicit and consider in choosing an evaluation method since the differences among the strategies can be a close call.
Careful observation strategy for pulmonary nodule
Careful observation, which involves radiographic surveillance with serial CT scans, is most useful when the probability of malignancy in a solitary pulmonary nodules is low (<5-10%, depending upon the patient’s comorbidities and preferences). This strategy is predicated on the assumption that growth rates, determined radiographically, can be used to distinguish benign from malignant lesions.
The only downside to this strategy is the hazard of delay that is inherent in waiting for a follow-up scan to detect evidence of growth – that is, the probability that a previously curable lesion will metastasize while the patient is waiting for the follow-up CT scan.
If follow-up CT imaging demonstrates unequivocal evidence of growth, it is highly likely that the lesion is malignant. If the patient is a surgical candidate, tissue diagnosis by surgical resection is warranted. Alternatively, a tissue diagnosis obtained by CT-guided FNA may be reasonable, provided that non-diagnostic results are further evaluated and treated appropriately. In patients with pulmonary reserve that is sufficiently limited to preclude surgery but in whom other treatment modalities are an option, a CT-guided fine-needle aspiration biopsy, followed by radiation therapy if the lesion is malignant, may be a reasonable alternative.
Limited follow-up is recommended (in 12 months) or follow-up when symptoms develop for patients who are not candidates for any type of curative treatment. If follow-up CT imaging demonstrates persistence of the lesion but does not demonstrate evidence of growth, the lesion can be followed with periodic CT scans, the optimal frequency and duration of which depend on several factors, including the size of the lesion, the presence of lung cancer risk factors, and whether the lesion is solid (as opposed to being a ground-glass opacity or a semi-solid lesion). (TableI)
For solid pulmonary nodules, the frequency of the follow-up scans is based primarily on the presence or absence of lung cancer risk factors and size. Traditional teaching has suggested that radiographic stability for two years is sufficient to call a lesion benign based on the observation that most malignant nodules’ doubling times are 20-300 days.
However, the duration of follow-up for ground-glass opacities and semi-solid nodules is longer because bronchioloalveolar carcinomas (BAC) frequently appear as ground-glass opacities. BAC is associated with very long doubling times – in the range of 42-1,486 days in one study. In a study of doubling time based on radiographic appearance, the doubling time of pure ground-glass opacities averaged 813 days, semi-solid (mixed GGO and solid) lesions averaged 457 days, and solid lesions averaged 149 days.
Therefore, the traditional two-year stability rule may prove insufficient to rule out malignancy in these cases. There is a paucity of evidence in this area as to what constitutes optimal frequency of follow-up, but expert opinion suggests that follow-up out to three years or longer may be necessary.
Frequency and duration of CT imaging for pure ground-glass opacities (GGOs) and semi-solid lesions
No additional follow-up CT is warranted for GGOs less than 5 mm in size since these are usually atypical adenomatous hyperplasia. PET scan is not useful for these lesions.
For pure GGOs larger than or equal to 5 mm and smaller than 10 mm in size, follow-up CT is warranted in 3-6 months to document the stability, regression, or progression of the lesion. If the lesion grows or if a solid component develops, the chance of malignancy is high and further evaluation for resection is warranted. PET may be useful if a solid component develops, but if the lesion is unchanged, surveillance imaging should be conducted yearly.
Optimal duration of surveillance is unknown, but it has been recommended that a minimum of three annual studies be performed to document stability since doubling times for these lesions can be prolonged. PET scan is not warranted for pure GGOs because of their small size since a negative PET scan does not have sufficient negative predictive value. In addition, there is a very low likelihood of associated metastatic disease, reducing PET’s usefulness for pure GGOs.
For pure GGOs that are larger than 10 mm, follow-up CT is warranted in 3-6 months to document the stability, regression, or progression of the lesion. If the lesion is unchanged, consideration of resection is warranted if the patient is a surgical candidate. PET scan is not warranted for these patients either.
Semisolid lesions (mixed appearance with both GGO and partially solid component)
For semisolid lesions with a mixed appearance of any size, follow-up CT is warranted in 3-6 months to document the stability, regression, or progression of the lesion. If the lesion grows or if the percentage of the lesion that is solid grows, the probability of malignancy is high.
If the lesion is unchanged, the probability of malignancy is still sufficiently high to warrant further evaluation. PET or PET/CT in these cases is warranted since there is an increased likelihood that these lesions are invasive adenocarcinomas and that the patient will benefit from preoperative staging.
The role of CT-guided FNA in these cases is limited and is determined by the pretest probability of cancer, the patient’s surgical risk, and his or her preferences. In low-risk surgical patients, surgical wedge biopsy and resection, as warranted, is often best since the pretest probability of malignancy is high and a negative CT-guided FNA does not have sufficient negative predictive value to exclude malignancy. In some select patients at high risk of surgical complications, CT-guided FNA with core biopsy may be useful, although the negative predictive value may be limited.
Bronchoscopic techniques for the diagnosis of lung cancer
Conventional bronchoscopy uses a variety of instruments, including transbronchial biopsies, endobronchial biopsies, bronchial brushing, and bronchoalveolar lavage, to establish a diagnosis of lung cancer. In general, it is best to utilize all of these techniques in any given patient in order to maximize the diagnostic yield.
The presence on CT of an air-bronchogram in the nodule is associated with a higher diagnostic yield for lung cancer (approximately 70%); in such cases, bronchoscopy is often the best option to diagnose and stage the patient since it allows simultaneous staging of the mediastinal lymph nodes with endobronchial ultrasound (EBUS)-guided TBNA and biopsy of peripheral lesions.
Recently, advanced diagnostic techniques like electromagnetic navigation and guidance and radial EBUS have been developed.
Electromagnetic navigation allows for diagnostic yields of 38-74%, radial EBUS provides a sensitivity of about 73%, and in one study the combination of radial EBUS plus electromagnetic navigation was superior to either technique alone. With both conventional and advanced diagnostic bronchoscopy, overall safety is good. Retrospective studies of conventional bronchoscopy have reported rates of less than 1% for major complications like bleeding, respiratory failure, and cardiac arrest or arrhythmia. However, prospective studies have reported slightly higher complications, with pneumothorax rates of 5-8% in some studies of advanced diagnostic bronchoscopy techniques.
Electromagnetic navigation and guidance combines bronchoscopy with CT virtual imaging by generating an electromagnetic field around the patient. A steerable electromagnetic sensor is passed through the bronchoscope, and as long as the sensor is within the electromagnetic field, its location is known, even if it is not within visual range of the sensor. The sensor can then be maneuvered to the lesion using the CT data.
Uncontrolled studies in carefully selected patients have demonstrated a diagnostic yield of 38–74% with a great deal of heterogeneity among different studies. Predictors of success include the presence of a CT bronchus sign, low divergence (defined as the average error between the real position of the probe and the projected position of the probe based on the CT-based virtual reality simulation), middle lobe location, or a non-lower lobe location.
Although one randomized trial demonstrated that the combination of EBUS and electromagnetic navigation was superior to either method alone, no randomized studies have yet compared electromagnetic navigation with conventional bronchoscopy. The studies also report results obtained only by experienced and highly skilled operators in carefully selected patients.
Endobronchial ultrasound (EBUS)
The two forms of endobronchial ultrasound are linear EBUS and radial EBUS. Linear EBUS, which uses a linear probe built into the bronchoscope itself, offers the advantage of imaging the needle in real time and is useful in sampling of mediastinal lymph nodes. However, linear EBUS can also be useful in establishing a diagnosis, either by sampling involved lymph nodes or as a means to guide needle biopsies of lesions that happen to be adjacent to a large airway. The current size of the linear EBUS bronchoscope limits its ability to travel out into the periphery.
For most patients, the linear EBUS bronchoscope will reach to the lobar bronchi, but it will be too large to pass very far into the segmental or smaller bronchi.
Radial EBUS, which uses a small probe that is passed through the instrument channel of a bronchoscope, is useful for diagnosis of peripheral lesions. A recent meta-analysis of sixteen studies using bronchoscopy with radial EBUS for peripheral lesions demonstrated a pooled sensitivity and specificity of 73% and 100%, respectively. Of the sixteen studies, seven had sufficient data to stratify their results based on size. In nodules less than 25 mm in size, the pooled sensitivity was 71%, while in nodules larger than or equal to 25 mm in size, the pooled sensitivity was 75%.
The diagnostic yield of peripheral radial EBUS also depends on the bronchoscopist’s ability to enter the lesion. When the EBUS probe is confirmed as being inside the lesion, diagnostic yield is about 83%, while when it is adjacent to the lesion, the yield is about 61%. When it is not in or adjacent to the lesion, the yield drops to 4%.
Lung cancer screening
Molecular markers for in sputum, blood, and bronchial brushings have been studied, but none are currently suitable for clinical application.
Screening with routine yearly chest x-rays has also proven ineffective at reducing mortality. However, advances in multidetector CT have made low-dose helical CT screening feasible for patients with lung cancer. Several observational studies have demonstrated that low-dose helical CT of the lung detects more nodules and lung cancers, including early stage cancers, than chest x-rays do.
The National Lung Screening Trial (NLST), a randomized multicenter trial, evaluated whether screening with low-dose CT, rather than chest radiography, would reduce mortality from lung cancer. The NLST enrolled 53,454 persons at high risk for lung cancer. Participants had to be between 55 and 74 years old, have at least a thirty-pack-year history of tobacco use, and had to have been active smokers sometime within the prior fifteen years.
Patients in the low-dose CT arm had nodules identified in 24.2% of cases, as compared to 6.9% in the chest x-ray arm, over three rounds of imaging. Most nodules identified were not malignant; the false positive rate was 96.4% in the CT arm and 94.5% in the chest x-ray arm. The incidence rate of lung cancer in the CT group was 645 cases per 100,000 person-years versus 572 cases per 100,000 person-years in the chest x-ray group. There were 247 deaths from lung cancer per 100,000 person years in the CT group, as compared to 309 deaths from lung cancer per 100,000 person years in the chest x-ray group (relative risk reduction was 20.0%; 95% CI 6.8-26.7%; p=0.004).
Death from any cause was also lower in the CT group than in the chest x-ray group (relative risk reduction 6.7%; 95% CI 1.2-13.6%; p=0.02). Most nodules identified were followed with serial CT scans using a careful observation strategy. Overall, complications from invasive diagnostic procedures because of the screening were uncommon. Initial analyses of the cost-effectiveness of low-dose CT screening in the NLST suggest that it may be cost effective, with an overall estimate of $81,000 per Quality Adjusted Life Year (QALY). However, the cost-effectiveness varied widely in subgroup analysis and the cost-effectiveness of screening outside the trial setting will depend largely on which patients are selected for screening. Given the available evidence, in suitable high-risk patients similar to those included in the NLST, screening with low-dose CT is beneficial.
What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of lung cancer?
If you decide the patient has lung cancer, how should the patient be managed?
What is the prognosis for patients managed in the recommended ways?
What other considerations exist for patients with lung cancer?
What’s the evidence? (Provide an Annotated Bibliography. Follow the style of The New England Journal of Medicine.)
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- What every physician needs to know:
- Are you sure your patient has lung cancer? What should you expect to find?
- Beware: there are other diseases that can mimic lung cancer
- How and/or why did the patient develop lung cancer?
- Which individuals are of greatest risk of developing lung cancer?
- What Laboratory studies should you order to help make the diagnosis, and how should you interpret the results?
- What imaging studies will be helpful in making or excluding the diagnosis of lung cancer?
- What are the role and performance characteristics of chest CT for lung cancer?
- What patterns of calcification are associated with benign lung nodules and which ones are more likely to be malignant?
- What are the role and performance characteristics of positron emission tomography (PET)?
- NSCLC and multiple nodules
- Location of NSCLC and the TNM system
- What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of lung cancer?
- What diagnostic procedures will be helpful in making or excluding the diagnosis of lung cancer?
- Diagnostic strategy for lung cancer
- Pulmonary nodule evaluation and management
- Careful observation strategy for pulmonary nodule
- Frequency and duration of CT imaging for pure ground-glass opacities (GGOs) and semi-solid lesions
- Bronchoscopic techniques for the diagnosis of lung cancer
- Lung cancer screening
- What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of lung cancer?
- If you decide the patient has lung cancer, how should the patient be managed?
- What is the prognosis for patients managed in the recommended ways?
- What other considerations exist for patients with lung cancer?