Overview
Lung cancer is the leading cause of cancer-related deaths in men and women worldwide. The incidence of lung cancer in women has increased even faster than the overall incidence has, reflecting the increased use of tobacco among women in the past 30 years.[1, 2, 3]The most important prognostic indicator in lung cancer is the extent of disease. The Union Internationale Contre le Cancer (UICC) and the American Joint Committee for Cancer Staging (AJCC) developed the tumor, node, and metastases (TNM) staging system. This system takes into account the degree of spread of the primary tumor, represented by T; the extent of regional lymph node involvement, represented by N; and the presence or absence of distant metastases, represented by M. The TNM system is used for all lung carcinomas except small cell lung cancers (SCLCs), which are staged separately.
Non–small cell lung cancer (NSCLC), for which the TNM system is the most widely used staging scheme, accounts for approximately 75% of all lung cancers. NSCLC is subdivided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Despite their histologic and clinical differences, these carcinomas share a similar prognosis and are managed in a similar way. (See the images below.)
Image of a 1.8-cm peripheral carcinoma in the lingula, stage T1. 
Right middle lobe peripheral carcinoma, 3.5 cm in diameter, stage T2. 
Right apical carcinoma, stage T3. 
Right hilar mass invading the mediastinum, stage T4, with mediastinal lymphadenopathy, N3. Computed tomography (CT) scan screening can detect most cases of lung cancer. Surgery is the treatment of choice for NSCLC if the primary tumor is resectable and if metastatic disease is absent. Chemotherapy and radiation therapy are used to treat tumors that are unresectable because of intrathoracic spread or distant metastases. (SCLC metastasizes early and has a worse outcome than NSCLC.) For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Lung Cancer, Understanding Lung Cancer Medications, and Non-Small-Cell Lung Cancer.
Staging of Primary Tumors
The stages in the TNM system represent the nature and extent of spread of a neoplasm and, thus, the therapeutic options and prognosis in individual patients. Stages also provide a standard by which various therapies can be compared. A combination of clinical, laboratory, radiologic, and pathologic investigations are used to stage various neoplasms.[4, 5]Conventional chest radiography
Conventional chest radiographs (CXRs) usually demonstrate the size of the lung tumor, especially in peripheral lesions. Central tumors may be associated with atelectasis or obstructive pneumonitis. The proximal extent of central tumors is determined with bronchoscopy.CXRs may also show a pleural effusion, direct extension into the chest wall with destruction of the ribs or vertebrae, phrenic nerve involvement with elevation of a hemidiaphragm, or mediastinal widening due to lymphadenopathy. In the absence of these signs, CXRs are unreliable in detecting invasion of the chest wall, diaphragm, or mediastinum, and CT or MRI is required to assess these conditions.
Computed tomography scanning
Contrast-enhanced helical CT scanning of the thorax and abdomen, including the liver and adrenal glands, is the standard radiologic investigation for staging lung cancers. The primary tumor should be measured by using lung window settings in 2 dimensions: the maximum long axis and the largest diameter perpendicular to the long axis.[6, 7]CT scanning reliably depicts mediastinal invasion, provided that the tumor surrounds the major mediastinal vessels or bronchi. A tumor that abuts the mediastinum cannot be considered invasive, even if the fat plane between the mediastinum and mass is obliterated.
CT scan criteria for resectability include the following:
- Contact between mass and mediastinum of less than 3 cm
- Circumferential contact between the mass and aorta of less than 90°
- Presence of a fat plane between the mass and mediastinum
- Involvement of the carina
- Tumor surrounding, encasing, or abutting the aorta. Main or proximal portions of the right or left pulmonary arteries, or esophagus by more than 180°
Magnetic resonance imaging
MRI is superior to CT in assessing the pericardium, heart, and great vessels. Coronal images are useful in demonstrating the extent of tumor in the subcarinal region, aortopulmonary window, and superior vena cava. However, it is limited by poorer spatial resolution, as compared with that of CT, and by cardiac and respiratory motion artifacts; however, the magnitude of these limitations has diminished with newer MRI scanners.MRI may be used instead of CT in patients who have had previous adverse reactions to iodinated contrast media and in patients with significant renal impairment, because MRI does not require the use of intravenous enhancement with iodinated contrast media.
The overall difference in accuracy between MRI and CT is not significant. The sensitivity of CT is 63%, and that of MRI is 56%. In the distinction of T3 and T4 tumors from less extensive tumors, the specificity of CT is 84%, and that of MRI is 80%.
Positron emission tomography scanning
The role of positron emission tomography (PET) scanning has become more widespread since the turn of the 21st century. It is indicated in the assessment of indeterminate pulmonary nodules and staging. Fluorodeoxyglucose (FDG)-PET is superior to CT in differentiating between malignant and benign tumors. The preoperative use of PET has led to a reduction in the number of unnecessary thoracotomies in patients considered to be operable on the basis of CT and clinical criteria. The combination of CT and PET scanning improves radiotherapy planning and it is to be expected that combined CT-PET–guided planning devices will further refine 3-dimensional conformal radiotherapy.[8, 9, 10, 11]Staging of Mediastinal Lymph Nodes
Hilar (N1), ipsilateral (N2), or contralateral (N3) mediastinal lymph node metastases are often present at the time of presentation. The N stage is important, because it determines the prognosis and the suitability of curative surgery. On CXRs, CT scans, and MRIs, nodal enlargement may indicate nodal involvement; however, this finding may be inaccurate. Normal-sized nodes may contain metastases, and nodes may be enlarged due to inflammatory causes although they contain no malignant cells. Furthermore, the classification of nodes and the normal range of the size of mediastinal nodes have been disputed.On the accepted lymph node map described by the AJCC and UICC in 1997, nodes in position 10 are designated as hilar nodes. The short-axis diameter is the most reliable measurement of lymph node size on CT scans. A short-axis diameter greater than 10 mm is abnormal regardless of the nodal station.
Conventional chest radiography
Chest radiography is inferior to CT scanning in the detection of mediastinal lymph node metastases. It has a sensitivity of only 10-30%, although its specificity (90%) is higher than that of CT scanning.Computed tomography scanning
The visualization of mediastinal nodes is facilitated by the use of spiral or multisection CT, thin (5-mm) sections, the presence of mediastinal fat, and intravenously administered contrast material.The reported sensitivity and specificity of CT scanning in the detection of mediastinal nodes vary considerably, with ranges of 40-84% and 52-80%, respectively. This variability reflects interobserver variability and differences in the size criteria for abnormal lymph nodes, in patient populations, and in the diagnostic criterion standard. CT scanning is more specific in populations in Europe with a low incidence of granulomatous disease than it is in populations in the United States, which have a high incidence of histoplasmosis; rates are 80-90% and 50-70%, respectively.
The negative predictive value of CT scanning is about 85%; as a result, patients with normal mediastinal appearances undergo thoracotomy. Mediastinoscopy or thoracoscopy is required during biopsy of enlarged noncalcified lymph nodes before surgery is ruled out.
Magnetic resonance imaging
Like CT scanning, MRI size criteria are used to identify nodal involvement, and these are comparable to those used at CT scanning. However, MRI can be used to distinguish nodes from vessels without intravenous contrast enhancement. Also, direct imaging in the sagittal and coronal planes is possible; this is helpful in the assessment of the subcarinal and aortopulmonary regions.Positron emission tomography scanning
Unlike MRI and CT scanning, PET scanning does not rely on the anatomic assessment of nodes. It is primarily a metabolic imaging technique that relies on a biochemical difference between normal and neoplastic cells. Mediastinal nodes containing tumor have an increased uptake of FDG, a glucose analogue labeled with fluorine-18 (18 F), a positron emitter.Although its high cost and limited availability blunted the impact of PET scanning in Western countries, changes in regulations and reimbursement in the United States have increased the use of this modality and access to PET centers.
PET is superior to CT in the assessment of mediastinal nodal metastases. In patients with N2 disease, PET had a sensitivity of 83% and a specificity of 94%, compared with a sensitivity of 63% and a specificity of 73% with CT. The superiority of PET is even more marked in the assessment of hilar nodes, for which it has a 73% sensitivity and a 76% specificity, compared with an 18% sensitivity and an 86% specificity with CT.
FDG-PET enables accurate staging of regional lymph node disease in patients with stage I NSCLC. A negative PET scan in these patients suggests that mediastinoscopy is unnecessary and that thoracotomy may be performed. FDG-PET is justified as a supporting staging measure in cases presenting unclear differentiation between N2 and N3 after conventional staging.
In about 35% of cases first staged with CT, the disease is upstaged after subsequent PET, with resultant changes in management. Nevertheless, PET can produce some false-negative results. In one study, 5 of 39 patients with negative PET scans had a carcinoma, as revealed with pathologic staging. In 4 of these patients, correlation with CT findings led to the correct conclusion. Thus, PET and CT are complementary, because the visual information on CT enables anatomic discrimination between hilar and mediastinal nodes and more accurate localization of the hot spots. The sensitivity of PET combined with CT was 93%, and the specificity was 97%.
Studies suggest that FDG-PET is more sensitive but less specific in cases in which lymph node enlargement is present on CT scan. For patients with lymph nodes measuring 16 mm or more on CT and a negative FDG-PET result, the post-test probability for N2 disease was 21%. These patients should be scheduled for mediastinoscopy before possible thoracotomy to prevent too many unnecessary thoracotomies in this subset. However, for patients with lymph nodes measuring 10-15 mm on CT and a negative FDG-PET result, the post-test probability for N2 disease was only 5%. These patients should be scheduled for thoracotomy because the mediastinoscopy yield will be extremely low.
Staging of Distant Metastases
The detection of distant metastases is of crucial importance, because it usually implies that curative surgical resection of the primary tumor is contraindicated. Metastases occur in about 50% of patients with NSCLC. In patients with clinical or biochemical evidence of disease elsewhere, targeted imaging of those sites is performed. These sites include the brain, which can be examined with CT or MRI, and the skeleton, which can be examined with scintigraphy. Usually, these sites are not imaged in asymptomatic patients with NSCLC.The probability of metastases is highest for SCLC, which is 60-80% on presentation, and lowest for squamous cell cancers; the incidence increases with advancing stage. No such trend exists for cancer involving the other cell types. Adenocarcinoma tends to metastasize to the brain and adrenals early in its course.
Liver and adrenal metastases
The staging CT scan of the thorax is usually extended to include the liver and adrenal glands. CT scanning has a sensitivity of about 85% in the detection of liver metastases. Similar rates may be obtained with MRI and ultrasonography performed by experienced imagers. Ultrasonography is superior to CT scanning in distinguishing metastases from liver cysts, which account for most of the benign lesions seen on CT scans. (See the images below.)
Liver metastases of lung cancer. 
A 7-cm metastasis of lung cancer in the right adrenal gland. 
Sonogram shows a 6-cm right adrenal metastasis of lung cancer. Adrenal metastases are common and often solitary. They must be differentiated from adrenal adenomas, which occur in 1% of the adult population. Lesions smaller than 1 cm are usually benign. Metastases are usually larger than 3 cm; on nonenhanced CT scans, they have an attenuation coefficient of 10 HU or higher. Adenomas and metastases can also be distinguished by using MRI and PET scanning. Brain metastases
SCLC and adenocarcinoma are the most common sources of cerebral metastases. (See the images below.)
Contrast-enhanced CT scan shows 2 enhancing cerebral metastases of lung cancer in the left cerebral hemisphere. 
Image obtained in the same patient as in the previous image shows a third cerebral metastasis of lung cancer. MRI is superior to CT, especially in the depiction of the posterior fossa and the area adjacent to the skull base. However, the brain is not routinely imaged in asymptomatic patients with NSCLC, because the incidence of silent cerebral metastases is only 2-4%. Bone metastases
Technetium-99m (99m Tc) radionuclide bone scanning (see the images below) is indicated in patients with bone pain or local tenderness. The test has a 95% sensitivity for the detection of metastases but a high false-positive rate because of degenerative disease and trauma. The assessment of these metastases requires comparison of the bone scans with plain radiographs.
Isotope bone scan. 
Isotope bone scan. Hot spots due to bony metastases in the right second and ninth ribs. Spinal metastases may cause spinal cord compression. Because only about 5% of bony metastases detected with radionuclide scans are asymptomatic, routine preoperative bone scanning is not usually performed. Lung metastases
Pulmonary metastases (see the image below) from a primary NSCLC are uncommon on presentation, but they are present at autopsy in 20% of cases.
Pulmonary metastases from a primary bronchial neoplasm in the left lower lobe. Accurate preoperative diagnosis of small lung nodules depicted on CT scans is often difficult because they may be indistinguishable from granulomata and fibrotic nodules. Positron emission tomography scanning
In a study using PET scanning, FDG uptake was increased in 92% of proven adrenal metastases (23 of 25 patients) and was normal in the 8 benign lesions. Whole-body PET will probably decrease the number of adrenal biopsies performed for indeterminate adrenal lesions. In another study, unsuspected distant metastases were found in 11% of patients with primary lung carcinoma.Whole-body PET scanning is more accurate than thoracic or brain CT scanning, bone scintigraphy, or MRI in staging bronchogenic carcinoma. FDG-PET scan results have prognostic value and are strongly correlated with survival rates in patients who undergo treatment for lung cancer. Patients with positive FDG-PET results have a significantly worse prognosis than patients with negative results. Additionally, FDG-PET may be helpful in guiding treatment.
The introduction of combined PET-CT machines (see the image below) will affect the future workup and treatment of patients with cancer. These machines will also be used in radiation treatment planning. Integrated PET-CT improves the diagnostic accuracy of the staging of non–small-cell lung cancer.
Use of combined positron emission tomography (PET) and computed tomography (CT) in lung cancer staging. The central image is the result of combining the CT (left) and PET (right) images. Courtesy of Rambam Medical Center, Haifa, Israel and GE Medical Systems. In a study by Lardinois et al, integrated PET-CT scanning provided additional information in 20 (41%) of 49 patients beyond that provided by conventional visual correlation of PET and CT.[12] Tumor staging and node staging were significantly more accurate with integrated PET-CT than with CT alone, PET alone, or visual correlation of PET and CT; in metastasis staging, integrated PET-CT increased the diagnostic certainty in 2 of 8 patients. Staging of SCLC
SCLC has usually metastasized by the time of presentation. Extensive disease is present in more than 60% of patients. Surgery is an option in fewer than 5% of these patients, who have a small primary and no evidence of spread. Systemic chemotherapy is the main treatment, with response rates of 70% but cure rates of less than 5%.The distinction between limited and extensive disease is an important staging issue. The TNM system may be applied, but it is not directly relevant to management decisions. The objectives of staging in SCLC are to identify localized disease, for which radiation therapy may be suitable, and to quantify the extent of the disease before therapy.
Localized disease is defined as disease confined to 1 hemithorax that includes ipsilateral, contralateral, and/or supraclavicular nodes. Investigations include chest radiography; CT of the thorax, liver, and adrenal glands; cranial CT; bone scintigraphy; and bone marrow aspiration. The disseminated nature of SCLC makes whole-body survey techniques suitable for its evaluation.99m Tc-labeled monoclonal antibody fragment NR-LU-10 is used to detect an antigen present in most small cell cancers. Whole-body FDG-PET is a promising technique for detecting nodal disease. Combined MRI of the brain, spine, abdomen, and pelvis enables comprehensive staging with a single modality.
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