Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in men and women in the United States. It has surpassed breast cancer as the number one cancer killer of women. When it is diagnosed early, the prognosis is relatively good, with greater than a 60% 5-year survival for stage I disease compared to only 14% for all patients.106 The primary treatment of lung cancer is surgery (if it is indicated), but once nodal or distant metastases have developed, the correct type of therapy is adjuvant chemotherapy or radiation therapy. Correct staging is the mainstay of appropriate clinical management.
FDG-PET is a valuable noninvasive imaging test for detecting malignancy in solitary pulmonary nodules (SPNs), for staging or restaging NSCLC, for monitoring therapy, and for detecting residual or recurrent disease, and, finally, it provides prognostic information that is independent of lesion size, clinical stage, and cell type. It contributes to better informed medical decision making and more cost-effective medical care.
Diagnosis of NSCLC and Evaluation of Pulmonary Nodules
In the United States, approximately 150,000 indeterminate pulmonary nodules are discovered each year and between
30% and 50% of these are malignant.107,108 The incidence of cancer is not low enough to ignore it, nor is it high enough to decide to resect all nodules.
Chest radiography and CT scan can establish the benign nature of a lesion. Certain patterns of calcification (likelihood ratio, 0.07) or the presence of fat within the nodule or a low growth rate over 2 years (likelihood ratio, 0.01) are diagnostic of a benign etiology.109 CT provides some assessment of the likelihood of malignancy based on morphology and the presence of secondary findings, such as hilar or mediastinal adenopathy, but the vast majority of SPNs are indeterminate by radiographic or CT criteria.110
Biopsy by CT-guided transthoracic needle aspiration and bronchoscopy are helpful when positive, but because of sampling error, a benign result cannot exclude tumor. On the other hand, more invasive procedures, such as thoracoscopic or surgical biopsy, are associated with increased cost and mor-bidity.111 FDG-PET and contrast-enhanced dynamic CT (dCT) are accurate, noninvasive methods for diagnosing lung cancer.
Lowe et al.112 showed that FDG-PET has an overall sensitivity of 92% and a specificity of 90% in a study of 89 patients with nodules between 0.7 and 4.0 cm in diameter using a SUV cutoff of 2.5 or greater. Another criterion is if nodules are hyperintense compared to the mediastinum. With application of these two criteria, FDG-PET is approximately 96% sensitive and 80% specific for malignancy.
False-positive results may be caused by the increased gly-colytic activity within activated macrophages. Active granu-lomatous diseases can be FDG avid, such as tuberculosis,113 sarcoidosis,114 aspergillosis,115 histoplasmosis,116 or lipoid pneumonia and talc granulomata after pleurodesis,117 and pneumonitis and necrosis after high-dose radiation therapy.118 False-negative results can occur in some low-grade tumors, including bronchoalveolar carcinoma119 and bronchial carci-noid.120 Lesions that are near the limiting spatial resolution of the PET scanner (about 6 mm on newer systems) may be falsely negative because of the effect of the volume averaging (partial volume effect).
In a meta-analysis of 40 studies of 1,474 focal pulmonary lesions, Gould et al.121 reported a sensitivity of FDG-PET of 92% (95% confidence interval, range 89%-93%). They noted that in practice the sensitivity of 97% and a specificity of 78% decrease false-negative results. A nodule less than 1 cm should be considered worrisome for malignancy if any FDG accumulation is seen.
Dynamic CT uses intravenous iodinated contrast material to measure nodule perfusion, and this information provides an estimate of the likelihood of malignancy. A pre-
Benign (fat, calcium, etc.)
Indeterminate (< 8 mm)
contrast density measurement in Hounsfield units (HU) is obtained after a bolus injection of contrast material, and density measurements are performed at 1, 2, 3, and 4min. Enhancing nodules are presumed to be malignant and nonenhancing nodules are presumed to be benign. Using a threshold of 15 HU, this technique has a sensitivity of 98%, a specificity of 58%, an accuracy of 77%, and a very high negative predictive value (Swensen et al.122).
Nathan et al.,123 in a recent study of 36 patients, evaluated pulmonary nodules larger than 8 mm with both FDG-PET and dCT. The overall sensitivity and specificity for FDG-PET were 95% and 80%, respectively (using the criteria referred to above), and for dCT (with a cutoff of 15HU) were 100% and 27%, respectively.
Rohren et al.124 suggested a diagnostic algorithm as is shown in Figure 33.4. A negative dCT scan can confidently exclude malignancy, but after a positive dCT the patients should be followed with an FDG-PET study, because one-half of them can be shown to be truly negative with PET imaging. All this staging information can be used to plan subsequent diagnostic strategies (percutaneous needle biopsy or medi-astinoscopy) and to guide appropriate therapy.
One in 10 to 1 in 20 pulmonary nodules that are negative by FDG-PET imaging may, in fact, be malignant. One approach is to follow patients with a negative PET scan with serial CT examinations. A negative PET scan excludes highgrade lung carcinoma, so the risk of following patients over 1 to 2 years for nodule growth is low. Most of them are T1NOMO at the time of surgery.125
Zhuang et al.126 and Matthies et al.127 proposed dual-time PET imaging and thought this was suitable for nodules near the level of the cutoff value of 2.5 for SUV.
Relative FDG uptake in malignant nodules tends to increase between the scans, whereas the relative FDG uptake in benign nodules tends to remain stable or decrease slightly. Using a threshold of a 10% increase in SUV between 1 and 3 hours led to an increase in sensitivity for FDG-PET from 80% to 100%. The specificity, however, declined from 94% to 89% (Table 33.6). Demura et al.128 reported the significance of dual time point PET imaging in the staging of disease of the mediastinum.
The most standardized staging system is the TNM system. T denotes features of the primary mass, including size, location, and invasion, N denotes regional lymph node status, and M the presence or absence of metastatic disease.124
Because most patients have had a diagnostic CT before referral for FDG-PET, the PET scan is used mainly for assigning T stage (1) for the evaluation of the likelihood of malignancy in additional pulmonary nodules and to direct a confirmatory biopsy to them and (2) for the identification of malignant pleural effusions, which may be reactive or malignant, as CT cannot distinguish them.
In a study of 100 patients with newly diagnosed bron-chogenic carcinoma, Marom et al.129 compared staging with FDG-PET to staging obtained with a chest CT scan, a bone scan, and contrasted brain CT or MRI. For overall staging FDG-PET had an accuracy of 83%, whereas with conventional imaging it was 65% (P less than 0.005) (Table 33.7).
For mediastinal lymph nodes, PET had an accuracy of 85% and for conventional imaging it was 58%. The important point here was that 9% of PET-positive studies were CT negative and 10% of PET-negative studies were CT false positive. In N3 stage disease, the sensitivity and specificity of PET were 92% and 93%, respectively, and for CT they were 25% and 98% (P less than 0.005). In M stage, the PET scan
Benign (fat, calcium, etc.)
Indeterminate (< 8 mm)
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Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.