Imaging in Lung Cancer Staging

Updated: Sep 28, 2016
  • Author: Omar Lababede, MD; Chief Editor: Eugene C Lin, MD  more...
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Overview

Overview

Cancer of the lung is the leading cause of cancer mortality in men and women in the United States. [1] Cancer staging, which defines the extent of disease, is crucial in guiding treatment and determining prognosis. Staging also facilitates the assessment of response to therapy, communication between cancer centers, and clinical research. [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12]

Tumor, node, metastasis (TNM) staging is a consistent, reproducible description of cancers according to the extent of anatomic involvement. This system is based on defining the characteristics of the primary tumor (T), regional lymph node involvement (N), and the presence of distant metastases (M).

The revisions in the new seventh edition of TNM staging were proposed by the International Association for the Study of Lung Cancer (IASLC) staging project for lung tumors. These were accepted by both the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) . The new classification applies to small cell lung carcinoma (SCLC) and bronchopulmonary carcinoid tumors but is not used to stage sarcomas or other rare tumors. [13]

Imaging (especially computed tomography [CT], magnetic resonance imaging [MRI], and positron emission tomography [PET]) plays an important role in determining the pretreatment clinical staging (TNM or cTNM). CT of the chest alone is sufficient for stagin patients with pure ground glass opacities and an otherwise normal study, adn for patients with perpheral IA diease. Otherwise, PET/CT is recommended for patietns potentially eligible for curative treatment [14] . This clinical classification is a critical step in selecting and evaluating treatment. The pathological (postsurgical histopathological) classification (pTNM) is more precise in defining prognosis.

Guidelines on lung cancer screening have been issued by the following organizations:

  • American Cancer Society (ACS)
  • American College of Chest Physicians (ACCP)
  • National Comprehensive Cancer Network (NCCN)
  • U.S. Preventive Services Task Force (USPSTF)

The guidelines are in agreement that annual screening with low-dose, computed tomography (LDCT) scanning should be offered to patients aged 55 to 74 years and who have at least a 30 pack-year smoking history and either continue to smoke or have quit within the past 15 years. The USPSTF extends the recommended age range to 80 years, while the NCCN notes the existence of uncertainty about the upper age limit for screening and advises that screening beyond age 74 years may be considered as long as the patient's functional status and comorbidity allow consideration for curative intent therapy. [2, 3, 4, 5]

In addition, the NCCN guidelines recommend considering screening starting at age 50 in patients with at least a 20 pack-year smoking history and one or more of the following risk factors [4] :

  • Radon exposure (documented sustained and substantial)
  • Occupational exposure to lung carcinogens (eg, silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel fumes, nickel, coal smoke, soot)
  • Cancer history (lung cancer, lymphomas, cancers of the head and neck, or smoking-related cancers)
  • Family history of lung cancer in first-degree relatives 
  • Chronic obstructive pulmonary disease or pulmonary fibrosis

Small cell lung cancer staging

The Commission for Cancer (AJCC) adopted the new tumor, node, metastasis (TNM) system in 2010. [6] In addition, the 2011 National Comprehensive Cancer Network (NCCN) clinical practice guideline for SCLC incorporated TNM staging into its diagnostic and therapeutic algorithms; the NCCN suggested that researchers begin to use the TNM staging system in an effort to more accurately assess prognoses and to more specifically personalize therapeutic options. This recommendation is also reflected in the current NCCN guidelines. [7] However, the American College of Chest Physicians (ACCP) guidelines recommend use of both the TNM system and the Veterans Administration Lung Study Group (VALSG) system (limited-stage vs extensive-stage) to classify the tumor stage. [8]

SCLC consists of 2 stages: limited-stage and extensive-stage. Under the AJCC TNM staging system, limited-stage SCLC is defined as any T, any N, M0; the exception is T3-4, owing to multiple lung nodules that extend beyond a single radiation field.

Extensive-stage disease describes tumors that extend beyond the ipsilateral hemithorax, such as those that reach the contralateral lung and/or contralateral lymph nodes or that find their way to distant organs (eg, bone marrow). The AJCC TNM staging system classifies extensive-stage disease as any T, any N, M1a/b, and T3-4, due to involvement of multiple lung nodules.

The American College of Chest Physicians (ACCP) does not recommend positron emission tomography (PET) scanning in the routine staging of SCLC, although the NCCN guidelines recommend combined PET–computed tomography scanning if limited-stage disease or metastasis is suspected.

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TNM Staging

The TNM system defines the anatomic extent of the lung cancer based on assessment of the following 3 components:

  • The primary tumor (T)
  • The involvement of regional lymph nodes (N)
  • The presence or absence of distant metastasis (M)

The following images summarize the new staging system.

A chart summarizing the tumor, node, metastasis (T A chart summarizing the tumor, node, metastasis (TNM) staging system of lung tumors. The information is separated into 2 boxes based on the presence or absence of metastases. In cases with no distant metastases, the different stage groupings can be identified by intersecting appropriately matched horizontal (regional lymph node involvement) and vertical (tumor characteristics) columns. Unique stages such as stage 0 are defined separately. Reproduced with permission from the American College of Chest Physicians (Lababede O, Meziane M and Rice T, Seventh Edition of the Cancer Staging Manual and Stage Grouping of Lung Cancer: Quick Reference Chart and Diagrams. CHEST. January 2011;139(1):183-189).
Two illustrations summarizing the tumor, node, met Two illustrations summarizing the tumor, node, metastasis (TNM) staging system of lung tumors. The T classification can be defined by evaluating the size first (upper left), then upgrading the classification (if necessary) based on the presence of the other criteria of primary tumor invasion/extent (A, B, and C). The criteria of extent should not be used to assign a lower classification. The lower diagram can be used to define the N and M classification and to determine the corresponding stage. Note that N1, N2, N3, and the separate tumor nodule of M1a were depicted in the lower illustration based on a right-sided tumor (T). For left lung tumors, a mirror image of these descriptors should be used. Additionally, the endobronchial extension and local invasion (A and B of the criteria of extent) were shown in the upper illustration based on a left-sided tumor to simplify the drawing. Reproduced with permission from the American College of Chest Physicians (Lababede O, Meziane M and Rice T, Seventh Edition of the Cancer Staging Manual and Stage Grouping of Lung Cancer: Quick Reference Chart and Diagrams. CHEST. January 2011;139(1):183-189).

The new TNM staging classification includes the following:

  • The application of the TNM system to other types of lung tumors
  • Redefinition of the primary tumor classification by size: (1) Subdivision of T1 into T1a and T1b using the size threshold of 2 cm, (2) subdivision of T2 into T2a and T2b using the size threshold of 5 cm, and (3) reclassification of tumors larger than 7 cm as T3
  • Reclassification of the primary tumor with separate tumor nodule(s) in the same lobe as T3 (from T4 previously) and reclassification of the tumor as T4 if the separate tumor nodule(s) are in a different lobe of the same lung (previously M1)
  • Subdivision of M into M1a and M1b with differentiation between local intrathoracic and distant metastatic disease; the malignant pleural and pericardial effusions are reclassified from T4 to M1a; M1a also includes separate tumor nodule(s) in the contralateral lung
  • Changes to stage groupings: (1) Redesignation of T4N0M0 and T4N1M0 tumors from stage IIIB to stage IIIA, (2) T2bN0M0 tumors are grouped under IIA instead of IB, and (3) T2aN1M0 tumors are grouped under IIA rather than IIB
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T Classification of Primary Tumor

Imaging modalities are valuable in defining the T classification of the primary tumor by providing information about its size and local extent/invasion. Chest CT scanning has been the primary and most commonly used modality to achieve this task. This role has been enhanced since the introduction of multidetector CT (MDCT) scanning. This is primarily because of the ability of MDCT to generate thin sections in a shorter scan time, resulting in improvement of the spatial resolution and multiplanar reformation (MPR) capability. [15]

MRI and PET scanning provide additional crucial information for accurate classification in some cases. [16] Compared with CT scan, MRI has superior tissue contrast but it is more susceptible to cardiac and respiratory motion artifacts. It is also affected by low proton density, very short T2* values, and inhomogeneity of the magnetic field in the lungs. However, recent advances in MRI techniques and the use of gadolinium contrast media have enhanced the diagnostic capability of MRI in detecting and staging lung cancer. [17] MRI can be used to further delineate the findings of nonenhanced CT in patients with adverse reactions to iodinated contrast media or significant renal impairment. [18]

Chest radiography and ultrasound have limited utility in the staging of lung tumors.

Size of the primary tumor

The new staging system does not provide specific guidelines for the imaging-based measuring technique of the primary neoplasm. The maximal dimension of the lesion on multiplanar reconstructed CT scans (in lung window settings) is generally used. [19] In tumors with surrounding hemorrhage or changes of postobstructive pneumonitis and/or atelectasis, estimating the size of the primary neoplastic lesion by CT scanning can be challenging (especially on noncontrast CT). In some of these cases, PET scanning and MRI can delineated the tumor from the surrounding changes.

Chest radiography can demonstrate the size of the primary tumor, especially in peripheral lesions. However, its utility is limited in cases of central lesions or those with surrounding secondary processes. Additionally, chest radiography is less accurate than CT scanning in estimating the size of the peripheral tumors, owing to magnification effect and issues related to projection.

Extent and local invasion of the primary tumor

In clinical practice, the endobronchial extent of the primary neoplasm is primarily and accurately defined by bronchoscopy. Imaging, especially CT scanning and MRI, can suggest the extent of the tumor by delineating its endobronchial component or by demonstrating associated secondary changes such as postobstructive pneumonitis or atelectasis.

Visceral pleural invasion (VPI) is an important finding that advances the classification from T1 to T2. In the seventh edition of the TNM staging, the IASLC implemented a standardized definition of the visceral pleural invasion as extension beyond the elastic layer up to the visceral pleural surface (based on pathologic examination with elastic stains). [13] Invasion of the pleura into an adjacent ipsilateral lobe should be classified as T2. Imaging is limited in reliably confirming invasion in the presence of contact between the mass and the visceral pleura.

Recently, measurement of the ratio of the interface between the tumor and adjacent structure (arch distance) to the maximum tumor diameter has been suggested as a high performance criterion of pleural invasion. [20] A ratio greater than 0.9 achieved sensitivity and specificity of 89.7% and 96%, respectively.

The invasion of the chest wall can be reliably detected by CT only in cases with gross soft tissue or osseous involvement. Otherwise, CT is limited in assessing such invasion in less overt cases with contact between the mass and the chest wall. Detecting chest wall invasion by lung tumor is important for preoperative evaluation and planning. Although such invasion does not exclude surgery, it may alter the surgical approach. The following CT findings can suggest but do not confirm the invasion of the parietal pleura and chest wall:

  • Length of contact between the lesion and the chest wall of more than 3 cm
  • Relatively large area of contact between the mass and the chest wall, with the ratio of the lesion's diameter to the length on contact of more than 0.5
  • Obliteration of the extrapleural fat plane
  • Obtuse angle and/or pleural thickening at the margin of contact between the lesion and the pleura

MRI is more accurate than CT scanning in depicting chest wall invasion, especially in the superior sulcus region. However, the accuracy of both conventional CT and MRI in assessing chest wall invasion is relatively low. Emerging ultrasound, CT, and MRI dynamic techniques that assess the tumor movement in relation to the chest wall could be helpful in the confirmation of chest wall invasion but are not widely implemented. In a 2008 study, [21] ultrasound was more sensitive than CT in evaluating chest wall invasion, with sensitivity of 89% versus 42%. In another 2008 study about chest wall invasion detection by respiratory dynamic MRI, [22] the sensitivity and specificity were 100% and 82.9%, respectively. The false-positive cases in these 2 studies were mostly secondary to benign adhesions between the visceral and parietal pleura.

Plain radiography has a limited role in detecting chest wall invasion, except in the presence of large soft tissue mass or osseous destruction.

Mediastinal invasion by the primary tumor can be reliably depicted using CT scanning or MRI. This is one of the important criterion in staging lung cancer, since it can determine resectability of the tumor.

In some cases, mediastinal invasion can be grossly visible (eg, significant replacement of the fat by the soft tissue of the tumor or encasement of a vascular structure or other structures by the neoplasm). Otherwise, the contiguity of the tumor with the mediastinum does not necessarily imply invasion. It was suggested that although CT cannot confirm mediastinal invasion in such cases with certainty, it can separate masses that were likely to be technically resectable (no invasion or focal limited invasion). [23] This separation of the resectable lesions is based on the presence one or more following CT findings:

  • 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 the mediastinal structures

Using the reverse criteria is less reliable in predicting irresectability. For example, a fat plane between the mediastinum and mass can be obliterated not only by invasion, but also by technical factors (eg, motion artifacts and volume averaging). The presence of more than 3 cm of contact or more than 90° of encasement has low sensitivity in confirming invasion.

MRI can be used in cases with questionable CT findings, given its superior tissue contrast and multiplanar capabilities. In a study from 2013, the sensitivity in nonspecific CT, CT with contrast-enhancement, and MR angiogram for detecting mediastinal and hilar invasion where 78-90%, 73-87%, and 75-88%, respectively. [17] MRI can delineate infiltration or disruption of the extrapleural fat planes, which suggests chest wall invasion. This can be further enhanced by the administration of intravenous contrast and other nonemergent techniques such as dynamic cine MRI.

The combined PET/CT is more accurate than PET alone in detecting chest wall and mediastinal invasion. However, there is limited added value of PET/CT over CT in T assessment. [24]

Presence of additional/separate ipsilateral pulmonary nodules

The presence of additional separate tumor nodule(s) renders the tumor's classification as T3 if the nodule is in the same lobe of the primary tumor, or as T4 if the nodule is in a different ipsilateral lobe. A separate tumor nodule in the contralateral lung is considered M1a. CT is the primary modality to evaluate for additional tumor nodules. The differential diagnosis of a separate nodule on CT should include benign entities and synchronous primary tumor in addition to metastasis from the primary lesion. Synchronous primary tumors, which should have different histologic cell types or subtypes, are not considered as T4 but are classified according to the highest the T designation of the lesions with a number of nodules in parentheses. PET CT can further suggest a malignant nature of an additional nodule by demonstrating increased fluorodeoxyglucose (FDG) uptake.

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N Classification of Regional Lymph Nodes

Thoracic metastatic adenopathy is an important prognostic factor in lung cancer. Detecting nodal involvement is viable for surgical planning since tumors with contralateral mediastinal and hilar nodes are considered nonresectable. Although regional lymph node (N) classifications have not changed, a unified map of lymph node stations was adopted by the IASLC. The new map reconciles discrepancies among previous nodal mapping proposals and introduces the concept of lymph node zones. [13, 25]

Plain chest radiography

Plain chest radiography is inferior to CT scanning in the detection of mediastinal lymph node metastases. The visualization of mediastinal nodes on CT is facilitated by the use of spiral or MDCT scanning with thin slice thickness, the presence of mediastinal fat, and intravenously administered contrast material.

CT scanning

On CT scans, the short-axis diameter is the most reliable measurement of lymph node size. A short-axis diameter greater than 10 mm is considered abnormal. Nodal enlargement on imaging may indicate nodal metastatic involvement. However, normal-sized nodes may contain metastases, and nodal enlargement can be secondary to a variety of inflammatory causes.

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 criterion for abnormal lymph nodes, in patient populations, and in the diagnostic criterion standard. CT scanning is more specific in populations in Europe who have a low incidence of granulomatous disease, than it is in populations in the United States, who 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 considering surgery.

PET scanning

Unlike 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 a positron emitter (fluorine-18 [18 F]).

The combined PET/CT is more accurate in the tumor and node staging than that of conventional visual correlation of PET and CT scanning. [26] PET scanning is superior to CT scanning in the assessment of mediastinal and hilar nodal metastases. A large number of studies have validated the higher sensitivity and accuracy of FDG PET/CT compared with conventional CT in detecting metastatic nodal involvement. A meta-analysis compared the diagnostic performance of PET demonstration of mediastinal nodal metastases in patients with non–small cell lung cancer with that of CT (based on 14 studies of the first modalities and 29 the studies of the second). [27] In this study, the mean sensitivity and specificity were 79% and 91%, respectively, for PET and 60% and 77%, respectively, for CT.

False-negative PET CT can be seen with microscopic metastatic nodal involvement and false-positive PET/CT is commonly present with inflammatory reactive nodes. PET/CT can provide valuable information for the assessment of nodal stations that are inaccessible by mediastinoscopy. FDG-PET enables accurate staging of regional lymph node disease in patients with stage I non–small cell lung cancer. 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.

MRI

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. In addition, direct imaging in the sagittal and coronal planes is helpful in the assessment of the subcarinal and aortopulmonary regions.

One study demonstrated that STIR turbo SE imaging is at least as valid as coregistered FDG-PET/CT for quantitative and qualitative assessment of the N-stage for non–small cell lung cancer patients. The metastatic lymph nodes are recognized by having high signal intensity on this sequence, compared with the metastatic nodes, which have low signal intensity. In the same study, the reported sensitivity of 90.1% and accuracy of 92.2% were higher compared with those of the PET/CT. [28]

Diffusion-weighted imaging (DWI) is a promising MR technique in the staging of lymph node involvement. This technique was reported to be more accurate than PET/CT in differentiating inflammatory from metastatic FDG-avid nodes by demonstrating no restricted diffusion in the inflammatory lymphadenitis. However, this technique has limited spatial resolution and can be false positive with adenitis from mycobacterial infection. [17]

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M Classification of Distant Metastases

The detection of distant metastases is of crucial importance because it usually implies a poor prognosis. These patients are generally treated with chemotherapy and/or radiation, as curative surgical resection of the primary tumor is not a consideration.

Metastases occur in about 50% of patients with non–small cell lung cancer. The probability of metastases is highest forsmall cell lung cancer, 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. 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 scanning or MRI, and the skeleton, which can be examined with scintigraphy. Usually, these sites are not imaged in asymptomatic patients with non–small cell lung cancer.

With recent advances in MRI, whole body MRI with DWI is emerging as a single, cost-affective imaging technique comparable to that PET/CT for staging patients with metastatic carcinoma. [17]

Intrathoracic metastasis (M1a)

The differentiation between benign and neoplastic pleural thickening/nodularity (a criterion for M1a) is a potential advantage of PET over conventional imaging. This is important since thoracocentesis can be falsely negative in 30-40% of patients with malignant pleural effusion. [24] Since PET/CT has high negative predictive value, it eliminates the need for repeated thoracocentesis or biopsies in patients with pleural abnormalities. Conversely, increased uptake on PET/CT in such patients indicates the need for further workup to evaluate for metastatic involvement.

Separate tumor nodule in the contralateral lung (another criterion for M1a) is generally detected first during the initial CT evaluation. PET/CT and MRI can further suggest the malignant nature of such lesions.

Extrathoracic metastasis (M1b)

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. 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 3-phase contrast-enhanced CT, MRI, and PET scanning.

MRI is superior to CT scanning in detecting brain metastatic involvement, especially in the depiction of the posterior fossa and the area adjacent to the skull base. PET/CT has low sensitivity for detecting brain metastases involvement, given the presence of a background of high glucose uptake by the normal brain tissue.

Technetium-99m (99mTc) radionuclide bone scanning is indicated in patients with bone pain or local tenderness. The test has 95% sensitivity for the detection of metastases but a high false-positive rate secondary to the increased tracer uptake by the commonly prevalent degenerative disease and posttraumatic changes. The assessment of metastases requires correlation of the bone scans with plain radiographs. 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. In a 2009 study, PET/CT was superior to bone scan in detecting osseous metastases of non–small cell lung cancer, with a lower incidence of false-positive and false-negative results. [29] . A 2012 meta-analysis reported an overall sensitivity and specificity of 92% and 98%, respectively, for osseus metastases on PET/CT, which was superior to both MRI and bone scan. [30]

Whole body FDG PET/CT is valuable in the evaluation for distant metastasis and can detect clinically unsuspected metastases in up to 25% of patient with non–small cell carcinoma. [31]

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