Bronchogenic Carcinoma

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Non-Small Cell Lung Cancer

Detection

A patient with bronchogenic carcinoma may report symptoms including cough, sputum production, or hemoptysis at first presentation for evaluation by a physician. Other patients have advanced disease and nonspecific systemic symptoms, including weight loss and weakness, at initial examination. Chest radiographs may show findings that suggest lung cancer. Still other patients report no symptoms related to lung cancer, and abnormal results on chest radiographs prompt further workup. In almost 40% of patients with lung cancer, the disease has spread outside the thorax.1

Whether earlier detection of lung cancer improves outcomes remains controversial. Randomized, controlled lung cancer screening studies performed in the 1970s did not show a reduction in the number of deaths from lung cancer in patients screened with chest radiography and sputum cytology when compared with controls who received either less-frequent chest radiography or advice that chest radiography and sputum cytology be performed once a year.2-4 This failure to demonstrate a reduction in lung cancer mortality occurred despite an increase in the detection of early-stage, resectable lung cancers and improved lung cancer survival in the experimental group screened every 4 months. Criticisms of these studies included insufficient statistical power, contamination of the control group, and a 25% noncompliance rate among the screened group.5 In the Mayo Lung Project and the Czechoslovak screening studies, the incidence of lung cancer in the experimental groups was significantly higher than in the control population, suggesting that the two groups were not balanced with regard to important variables that affect lung cancer risk.6 This discrepancy in incidence adversely affected calculated lung cancer mortality. The failure of screening chest radiography to improve the outcome in lung cancer occurred in multiple studies. A meta-analysis of screening studies enrolling a total of 245,610 subjects showed an 11% higher mortality from lung cancer when compared with less-frequent radiographic screening.7

A newer approach to lung cancer screening is low-dose helical CT, rather than conventional chest radiography. The Early Lung Cancer Action Project (ELCAP) recruited 1,000 high-risk individuals for baseline and annual repeat screening with low-dose helical CT.8,9 In 1999, Henschke et al. reported the results of 1,000 baseline screening CT examinations.8 Bronchogenic carcinoma was diagnosed in 27 individuals. Twenty-three of these patients had stage I disease; only 1 patient had unresectable disease. In 1,184 annual repeat screening examinations, malignancy was diagnosed in 7 individuals: 5 stage IA, 1 stage IIIA, and 1 small cell carcinoma.9

The conflicting analyses of earlier lung cancer screening trials and the advent of new technology capable of detecting early-stage lung cancer prompted the National Cancer Institute to fund a large-scale randomized, controlled lung cancer screening trial, the National Lung Screening Trial (NLST). In this trial, low-dose helical CT was compared with chest radiography in 50,000 participants at increased risk for lung cancer. Inclusion criteria required that participants be 55 to 74 years old and have at least a 30-pack/year cigarette-smoking history. Enrollment and incidence screening occurred between 2002 and 2004. Participants were randomized to either CT (experimental arm) or chest radiography (control arm) and received screening examinations once a year for 3 years. Follow-up will continue through 2009. In a subset of 10,000 participants, samples of blood, urine, and sputum were collected and archived to be available for further study using biomarkers for early detection of lung cancer.

Imaging Appearance Bronchogenic carcinomas have a variety of appearances on imaging studies, ranging from a solitary pulmonary nodule to

lobar consolidation. Some of these appearances strongly suggest specific cell types, despite considerable overlap.

Solitary Pulmonary Nodule

A solitary pulmonary nodule is defined radiographically as an opacity measuring less than 3 cm in diameter and surrounded by air-containing lung. Opacities that are larger than 3 cm in diameter are considered masses. The solitary pulmonary nodule presents a diagnostic challenge. Although most such nodules are benign, each must be further evaluated as a possible neoplasm. The interface between malignant nodules and the surrounding lung may appear smooth, lobulated, irregular, or spiculated. The margins of the solitary pulmonary nodule have been correlated with the incidence of malig-nancy.10 A nodule with spiculated margins has a higher likelihood of malignancy than does the smoothly marginated nodule. A peripheral solitary pulmonary nodule is a common presentation for adenocarcinoma of the lung. The nodule may be round or oval, with smooth, lobulated, or irregular margins (Figure 29.1). The nodule may cause distortion of the surrounding pulmonary architecture and retraction of the overlying pleura. The concept of scar carcinoma suggests that some lung cancers, particularly adenocarcinomas, may arise in preexisting lung scars. Fibrosis observed microscopically, however, may represent a desmoplastic reaction of the host tissue to the neoplasm.

CT screening for lung cancer has helped to clarify the early appearances and growth rates of malignant primary tumors in the lung.11 Nodules seen on high-resolution CT (HRCT), with 1.0- to 1.25-mm slice thicknesses, can be categorized on the basis of their CT attenuation as ground-glass opacity, mixed ground-glass and solid attenuation, and solid (Figure 29.2).12,13 Volume-doubling rates have been calculated as fastest for solid nodules at 149 days, intermediate for mixed figure 29.1. Axial computed tomography (CT) image (lung window setting) in a 69-year-old woman shows a spiculated, solid attenuation nodule (arrow) in the right upper lobe, typical for non-small cell bronchogenic carcinoma.

ground-glass/solid nodules at 457 days, and prolonged for ground-glass opacities at 813 days.11

Henschke et al. report a higher malignancy rate in nodules of mixed or ground-glass attenuation than in solid nodules found with screening CT.14 Ground-glass attenuation correlates with bronchioloalveolar cell carcinoma histology and with a more favorable prognosis.15 For this reason, some authorities recommend limited (wedge) resection for nodules of ground-glass attenuation and lobectomy for solid nodules.16

Lobe Resection Lung

figure 29.2. Axial CT images (lung window settings) show solitary pulmonary nodules in two different patients. (A) The solitary pulmonary nodule (arrow) in the right upper lobe demonstrates a mixed ground-glass and solid attenuation. (B) The solitary pulmonary nodule (arrow) in the left upper lobe of a different patient shows a ground-glass attenuation nodule. The ground-glass attenuation is suggestive of a bronchioloalveolar cell histology.

figure 29.2. Axial CT images (lung window settings) show solitary pulmonary nodules in two different patients. (A) The solitary pulmonary nodule (arrow) in the right upper lobe demonstrates a mixed ground-glass and solid attenuation. (B) The solitary pulmonary nodule (arrow) in the left upper lobe of a different patient shows a ground-glass attenuation nodule. The ground-glass attenuation is suggestive of a bronchioloalveolar cell histology.

Atelectasis and Postobstructive Pneumonitis

Atelectasis results from endobronchial obstruction or extrinsic compression of a bronchus. Atelectasis is a common presenting appearance of squamous cell carcinoma.17 Two-thirds of squamous cell carcinomas arise within main, lobar, or segmental bronchi.18 Although the atelectasis is most often segmental, it may be lobar or may involve the entire lung.17 The chest radiograph may demonstrate secondary signs of volume loss, with shift of the mediastinum to the involved side and elevation of the diaphragm. The central mass is often obscured by the collapsed lung.

When the upper lobe is collapsed, the trachea is deviated to the affected side, and the ipsilateral hilum is retracted superiorly. In atelectasis of the right upper lobe resulting from bronchogenic carcinoma, the minor fissure is classically distorted into a reverse S, the "S" sign of Golden.19 The lateral aspect of the minor fissure migrates cephalad, whereas the medial aspect of the fissure is tethered beneath the central neoplasm.

In some patients, the obstructed lobe is filled with inflammatory debris, and the classic signs of volume loss are not present. In these patients, the opacified lobe represents postobstructive pneumonitis, in which air bronchograms are typically absent. This radiographic finding can help to differentiate postobstructive pneumonitis from infectious pneu-monia.17 All cases of pneumonia occurring in adults should be followed radiographically to confirm resolution after antibiotic therapy and to exclude the presence of an underlying endobronchial lesion. Although squamous cell carcinoma is the neoplasm typically associated with lobar atelectasis, adenocarcinoma may also arise centrally. Enlarged hilar or mediastinal lymph nodes from any of the bronchogenic carcinomas, including both small cell and non-small cell, can extrinsically compress the bronchi and produce obstructive pneumonitis and atelectasis.

Airspace Opacification

The radiographic appearance of airspace opacification, mimicking pneumonia, can be caused by bronchioloalveolar cell carcinoma (BAC), a subtype of adenocarcinoma. BAC may be either focal (nodular) or diffuse disease. The diffuse form includes lobar or segmental consolidation, as well as multiple poorly defined pulmonary nodules. The pneumonic appearance of BAC is unique to this neoplasm. A diagnosis of BAC should be considered when a peripheral pneumonia seen on chest radiographs fails to clear after antibiotic therapy.

The consolidative form of BAC is seen on CT images as peripheral, segmental, or lobar airspace opacification with air bronchograms (Figure 29.3). The CT angiogram sign was first described with BAC and was initially thought to be useful in the distinction of BAC from pneumonia.20 The CT angiogram sign describes the CT appearance of enhancing pulmonary vessels within an area of homogeneously hypoattenuating pulmonary consolidation. Subsequent reports determined that the CT angiogram sign occurred in postobstructive pneu-monitis and pneumonia as well and therefore, was not a useful discriminator for the consolidative form of BAC.21,22 Aquino et al. and Jung et al. determined several CT features that were significant in the differentiation of pneumonic-type BAC from pneumonia.23,24 Features that suggest BAC include peripheral distribution, coexisting nodules, elongation and narrowing of the bronchi, widening of the bronchial angle, and bulging of the interlobar fissure.

Pancoast Tumor

Pancoast tumors make up less than 5% of all lung cancers. Their radiographic appearance and clinical presentation are unique. The tumor arises in the lung apex and typically involves, through direct extension, the parietal pleura and chest wall.25 The clinical syndrome described by Pancoast results from invasion of the tumor into the lower trunks of the brachial plexus and sympathetic chain. Patients experience shoulder pain, which may radiate down the arm, with eventual numbness and weakness in the C8 and T1 distribution, and atrophy of the muscles of the hand. Horner syndrome occurs in 20% of patients with Pancoast tumors and is caused by invasion of the paravertebral sympathetic chain by the tumor.25 The tumor may also invade the vertebral body and ribs.

A Pancoast tumor is suggested radiographically by a thickening of the pleura of at least 5 mm at the lung apex or by asymmetry of the apical caps of more than 5 mm.26,27 The tumor is sometimes detected when the lung apex is seen on images of the shoulder or cervical spine obtained to investigate a complaint of shoulder pain. Although Pancoast tumors can be visualized on axial CT images, MR imaging is the preferred modality.28,29 The coronal and sagittal planes of MR provide more accurate information for determining the extent of tumor invasion into the chest wall, including involvement of the brachial plexus, vertebral body, and neural foramen (Figure 29.4). MR angiography is complementary to MR imaging and can demonstrate displacement and encasement of the subclavian and brachiocephalic artery and vein.30

Rll Consolidation

figure 29.3. Axial CT (lung window settings) in a 63-year-old woman with the consolidative form of bronchioloalveolar cell carcinoma shows consolidation of the right lower lobe. The air bron-chograms in the right lower lobe appear stretched. Focal areas of consolidation and ground-glass attenuation are also present in the right middle lobe, lingula, and left lower lobe.

figure 29.3. Axial CT (lung window settings) in a 63-year-old woman with the consolidative form of bronchioloalveolar cell carcinoma shows consolidation of the right lower lobe. The air bron-chograms in the right lower lobe appear stretched. Focal areas of consolidation and ground-glass attenuation are also present in the right middle lobe, lingula, and left lower lobe.

Pancoast Radiotherapy Tequniqe

figure 29.4. An 82-year-old woman with a Pancoast tumor. (A) Axial CT (soft tissue windows) shows a mass (arrow) at the right lung apex, consistent with a Pancoast tumor. Coronal (B) and sagittal (C) magnetic resonance (MR) images more clearly identify the invasion of the chest wall and the vertebral body by the tumor (arrow).

Paraglottic Fat

Staging

Imaging Modalities Chest radiography remains the most frequently ordered radiographic examination. Its relatively low cost and widespread availability make it a very useful tool in the detection and diagnosis of thoracic disease. A chest radiograph with abnormal findings suggesting bronchogenic carcinoma typically prompts CT examination of the chest. The anatomic detail visible on CT images makes CT the examination of choice in such situations, as well as for patients with strong clinical evidence of thoracic disease despite normal chest radiographic results. CT is also useful to guide percutaneous transthoracic needle aspiration of thoracic masses. Although lacking the spatial resolution of CT, MR imaging allows imaging in coronal and sagittal planes and therefore is especially useful in the evaluation of patients with suspected invasion of the chest wall or diaphragm. In addition, MR

imaging can be helpful in evaluating mediastinal invasion and vascular involvement by tumor.

Positron emission tomography (PET) with fluorode-oxyglucose (FDG) uses the higher glucose consumption of hypermetabolic tumors to assist in differentiating between benign and malignant lesions and to determine the extent of disease. Because it relies on increased metabolism, FDG-PET imaging has improved the radiologic staging of lung cancer.31 Some of the limitations of PET, including spatial resolution and visual correlation with CT anatomy, are addressed in the newer dual PET/CT scanners. The addition of fusion imaging shows even better sensitivity and specificity for the detection of lymph node metastases and recurrent tumor.32,33

Primary Tumor (T) The high spatial resolution of CT makes it an excellent modality for assessing the size and extent of the primary

TABLE 29.1. TNM definitions.

T = primary tumor

T1 Tumor less than or equal to 3 cm in greatest diameter, surrounded by lung or visceral pleura without bronchoscopic evidence of invasion more proximal than the lobar bronchus

T2 Tumor with any of the following: greatest diameter more than 3 cm; involvement of main bronchus, at least 2 cm distal to the carina; invasion of visceral pleura; atelectasis or obstructive pneumonitis extending to the hilum but without involvement of entire lung

T3 Tumor of any size that directly invades any of the following: chest wall (includes superior sulcus tumors), diaphragm, mediastinal pleura, parietal pericardium; Tumor in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; Tumor with associated atelectasis or obstructive pneumonitis of the entire lung

T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, or carina; Tumor with a malignant pleural or pericardial effusion; Tumor with satellite tumor nodules in the ipsilateral primary-tumor lobe of the lung

N = regional lymph nodes

NO No regional lymph node metastasis

N1 Metastasis to ipsilateral peribronchial and/or hilar lymph nodes

N2 Metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes

N3 Metastasis to contralateral mediastinal or hilar lymph nodes; metastasis to ipsilateral or contralateral scalene or supraclavicular lymph nodes

M = distant metastasis

MO No distant metastasis

Ml Distant metastasis present

Source: Adapted from Mountain,40 by permission of Chest.

tumor (T). The diameter of the tumor determines its categorization as T1 and T2 (Tables 29.1, 29.2). Nodules 3 cm or smaller in greatest dimension are classified as T1 tumors. Masses larger than 3 cm are considered T2 tumors. A lesion that measures 3 cm or smaller and involves a bronchus is classified as T1 if it does not extend more centrally than the lobar bronchus. T2 tumors can involve a main bronchus but must be at least 2 cm distal to the carina. The 2-cm distance allows a surgeon to clamp the bronchus at the time of lobectomy. A T1 tumor must be surrounded by lung or visceral pleura without invasion of the visceral pleura; a T2 tumor may invade the visceral pleura. Involvement of the visceral pleura is a difficult determination with any imaging modality, as the visceral and parietal pleurae are not readily distinguishable in the absence of pleural effusion or pneumothorax. Visceral pleural invasion is associated with a higher frequency of mediastinal nodal involvement and a poorer prognosis.34,35 T2 tumors may also be characterized by lobar collapse or post-obstructive pneumonitis extending to the hilum. T3 tumors are those that invade, by direct extension, the chest wall, diaphragm, mediastinal pleura, or pericardium. Endo-

TABLE 29.2. International system for staging lung cancer.

Stage

TNM subset

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