Validation of two models to estimate the probability of malignancy in patients with solitary pulmonary nodules.

BACKGROUND: Effective strategies for managing patients with solitary pulmonary nodules (SPN) depend critically on the pre-test probability of malignancy. OBJECTIVE: To validate two previously developed models that estimate the probability that an indeterminate SPN is malignant, based on clinical characteristics and radiographic findings. METHODS: Data on age, smoking and cancer history, nodule size, location and spiculation were collected retrospectively from the medical records of 151 veterans (145 men, 6 women; age range 39-87 years) with an SPN measuring 7-30 mm (inclusive) and a final diagnosis established by histopathology or 2-year follow-up. Each patient's final diagnosis was compared with the probability of malignancy predicted by two models: one developed by investigators at the Mayo Clinic and the other developed from patients enrolled in a VA Cooperative Study. The accuracy of each model was assessed by calculating areas under the receiver operating characteristic (ROC) curve and the models were calibrated by comparing predicted and observed rates of malignancy. RESULTS: The area under the ROC curve for the Mayo Clinic model (0.80; 95% CI 0.72 to 0.88) was higher than that of the VA model (0.73; 95% CI 0.64 to 0.82), but this difference was not statistically significant (Delta = 0.07; 95% CI -0.03 to 0.16). Calibration curves showed that the probability of malignancy was underestimated by the Mayo Clinic model and overestimated by the VA model. CONCLUSIONS: Two existing prediction models are sufficiently accurate to guide decisions about the selection and interpretation of subsequent diagnostic tests in patients with SPNs, although clinicians should also consider the prevalence of malignancy in their practice setting when choosing a model.

Stage distribution in patients with a small (< or = 3 cm) primary nonsmall cell lung carcinoma. Implication for lung carcinoma screening.

BACKGROUND: Recently, there has been increased interest in the use of computed tomography (CT) for lung carcinoma screening. For this technique to be effective, small tumors must be detected at an earlier stage than large lesions. However, to the authors's knowledge, the relationship between the size of small primary (< or = 3 cm) neoplasms and disease stage at presentation has never been established clearly. The current study was performed to determine whether smaller lesions indeed have an earlier stage distribution compared with larger tumors. METHODS: The Duke University Medical Center Tumor Registry identified 620 patients (261 women and 359 men, with a mean age of 67 years) who presented with pathologically proven primary nonsmall cell lung carcinomas measuring < or = 3 cm between 1980-1999. Surgical, pathologic, and imaging information was reviewed retrospectively to confirm the size of the lesion and the disease stage at the time of presentation. The distribution of tumor size within each stage and the distribution of disease stage according to tumor size were determined. RESULTS: Tumors occurring in patients with TNM Stage IIIB disease were slightly larger than those found in patients with either more advanced or less advanced disease. However, there was no apparent statistically significant relation between the stage distribution and the size of the primary lesion. CONCLUSIONS: The current study data did not find a statistically significant relation between the size of small primary lung tumors and the distribution of disease stage at the time of presentation. This finding suggests that the detection of small tumors using screening CT may not result in a shift to an earlier disease stage distribution. A reduction in mortality needs to be demonstrated by appropriate clinical trials prior to the initiation of mass CT screening programs.

CT screening for lung cancer: not ready for routine practice.

Lung cancer continues to be a major worldwide health problem. Multiple strategies are being explored in an attempt to reduce lung cancer mortality, including a renewed interest in screening. Multiple low-dose spiral computed tomography (CT) trials have been proposed, as proponents predict that small nodules will represent early-stage disease and detecting them will ultimately translate into improvements in outcomes. At this time, however, only prevalence-screening data are available, and it remains to be seen if CT will truly reduce mortality. The appropriate hypothesis-driven studies still must be performed and the results carefully analyzed before CT screening for lung cancer can be accepted as the standard of care.

Correlation of FDG-PET imaging with Glut-1 and Glut-3 expression in early-stage non-small cell lung cancer.

PURPOSE: To correlate FDG activity on PET with the expression of glucose transporter proteins Glut-1 and Glut-3 in patients with early stage non-small cell lung cancer (NSCLC). METHODS: Over a 5 year period, all patients with a PET scan and clinical stage I NSCLC underwent an immunohistochemical analysis of their tumor for Glut-1 and Glut-3 expression. The amount of FDG uptake in the primary lesion was measured by a standardized uptake ratio (SUR) and correlated with immunohistochemical results. RESULTS: Seventy-three patients with a mean age of 66 years had clinical stage I disease. The final pathologic stage showed 64 patients with stage IA/B disease, eight with stage IIA disease, and one patient with pathologic stage IIIA (T1N2) disease. Glut-1 transporter expression was significantly higher than Glut-3 (P<0.0001), and although there was some association between the SUR and Glut-1 (P=0.085) and SUR and Glut-3 (P=0.074) expression, this did not reach statistical significance. CONCLUSIONS: Glut-1 and Glut-3 transporter expression did not demonstrate a statistically significant correlation with FDG uptake in potentially resectable lung cancer. It appears that these transporters alone do not affect the variation in FDG activity in early stage NSCLC.

Integration of peripheral blood biomarkers with computed tomography to differentiate benign from malignant pulmonary opacities.

Our purpose was to determine whether peripheral blood biomarkers MUC1 and CK19 could be used to complement imaging studies in differentiating benign from malignant indeterminate pulmonary nodules or masses detected on computed tomography CT. One hundred and eighteen patients had a thoracic CT and blood drawn for tumor marker reverse transcriptase-polymerase chain reaction analysis. Thirty-five of the 118 patients had an indeterminate pulmonary nodular opacity on CT, and the findings then were correlated with the reverse transcriptase-polymerase chain reaction results. The sensitivity and specificity for the markers in determining malignancy was calculated. Thirteen of the 35 opacities on CT proved to be benign, and 22 proved to be lung cancer. Among the patients with indeterminate pulmonary abnormalities, polymorphic epithelial mucin protein 1 had a sensitivity and specificity for lung cancer of 100% and 46%, respectively. Cytokeratin 19 had a sensitivity and specificity for lung cancer of 95% and 8%, respectively. These preliminary data showed that serum biomarkers polymorphic epithelial mucin protein 1 and cytokeratin 19 were not specific for lung cancer, although patients with an indeterminate pulmonary abnormality and negative markers were unlikely to have lung cancer. Integration of imaging studies with the appropriate biomarkers may prove useful in evaluating indeterminate pulmonary nodules or masses.

Identification of small lung nodules at autopsy: implications for lung cancer screening and overdiagnosis bias.

PURPOSE: Unsuspected cases of lung cancer are reported to be uncommon in autopsy series, and these data have been used to suggest that indolent tumors are rare and that overdiagnosis bias is not an important factor in lung cancer screening. The purpose of this study was to determine if a retrospective autopsy review is indeed accurate in identifying all small lung nodules on CT, and thus provide a true estimate of unsuspected lung tumors. MATERIALS AND METHODS: We identified all 1047 patients who had an autopsy at our institution from 1994 to 1998. We then reviewed the patients radiology records and found 187 patients with a thoracic CT within 2 months of the postmortem examination. All 187 CT reports were reviewed in order to identify patients with at least one pulmonary nodule. CT studies with reports that described a nodule(s) were then re-reviewed to confirm presence and location of the nodule(s). The CT findings were than compared to the autopsy report to determine if the postmortem examination indeed found the nodule(s). RESULTS: 28 autopsy patients had at least one pulmonary nodule identified on their thoracic CT no more than 2 months before death. Nineteen patients (68%) had nodule(s) recorded on the autopsy report, two ( approximately 10%) of which proved to have undiagnosed squamous cell carcinoma. Nine patients (22%) had no mention of pulmonary nodules seen on the CT recorded on their autopsy report. CONCLUSIONS: This study suggests autopsies do not identify all small pulmonary nodules found at CT. The true incidence of clinically insignificant lung cancer is thus uncertain, and overdiagnosis bias in lung cancer screening may be more important than previously recognized.

FDG-PET imaging in patients with paraneoplastic syndromes and suspected small cell lung cancer.

Paraneoplastic syndromes may be the presenting clinical manifestation of small cell lung cancer. In some cases, however, confirming the diagnosis can be difficult because findings on conventional imaging studies can be subtle or nonspecific. This study examined the utility of fluoro-2-deoxy-glucose positron emission tomography (FDG-PET) in identifying clinically suspected small cell lung cancer in patients with paraneoplastic syndromes. FDG-PET appears to be very useful in localizing suspected small cell lung cancer in patients presenting with paraneoplastic syndromes.

Design of a novel small peptide targeted against a tumor-specific receptor.

EGFRvIII is the most common deletion variant of the epidermal growth factor receptor and is found in cancers of the brain, breast, ovary, and lung. The complete absence of the receptor in healthy tissues makes it an ideal tumor marker. We sought to design a peptide ligand against EGFRvIII for development as a diagnostic imaging agent. We used the concept of hydropathic complementarity to search for sequences whose amino acid sidechains display a reciprocal pattern of hydropathicity to those of the deletion junction of EGFRvIII. The resulting peptide (PEPHC1) was synthesized and tested for binding to EGFRvIII and EGFR. In in vitro assays, PEPHC1 bound the recombinant EGFRvIII extracellular domain or full-length EGFRvIII solubilized from cell membranes in preference to native EGFR. These results demonstrate the utility of hydropathic complementarity as a basis for the design of highly specific ligands that may prove useful as tumor-targeting agents.

FDG PET of pleural effusions in patients with non-small cell lung cancer.

OBJECTIVE: We determined the ability of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to differentiate benign and malignant pleural effusions in patients with non-small cell lung cancer. MATERIALS AND METHODS: Over a 6-year period, we reviewed all patients with primary non-small cell lung cancer and a pleural effusion on staging CT who underwent FDG PET. We examined 25 patients (18 men and seven women; age range, 37-86 years; mean age, 65 years). FDG PET revealed positive findings if pleural activity was greater than background mediastinal activity; FDG PET revealed negative findings if pleural activity was the same as or less than background mediastinal activity. Results of FDG PET were correlated with pathologic diagnosis determined with thoracentesis or pleural biopsy. RESULTS: All patients had effusions on the same side as the primary tumor. Twenty-two patients had a malignant pleural effusion confirmed with thoracentesis (n = 19) or biopsy (n = 3). FDG PET revealed positive findings in 21 patients and negative findings in one. Three patients had no evidence of malignancy in the pleural space determined with cytologic findings (n = 2) or biopsy results (n = 1). FDG PET uptake revealed positive findings in one of these patients and negative findings in two. Therefore, of 22 patients with positive findings on FDG PET, 21 had pleural metastases, and of three patients with negative findings on FDG PET, one had metastases. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FDG PET for detecting pleural metastases were 95%, 67%, 95%, 67%, and 92%, respectively. CONCLUSION: This study suggests that FDG PET may be useful in improving staging evaluation in patients with non-small cell lung cancer and a pleural effusion. Increased pleural FDG uptake usually indicates pleural metastases; however, because the number of benign effusions studied was small, the relevance of negative findings on FDG PET in this setting is uncertain.

Non-small cell lung cancer: FDG PET for nodal staging in patients with stage I disease.

PURPOSE: To determine the accuracy of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in the evaluation of regional lymph nodes in patients with stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Imaging and clinical findings obtained during 5 years in 84 patients (mean age, 66 years) were reviewed. Patients had thoracic computed tomographic findings of stage I NSCLC, an FDG PET study, and histopathologic proof of lung cancer. At the time of diagnosis, disease stage was assigned on the basis of FDG PET results and was compared with the histopathologic stage to determine the accuracy of PET. RESULTS: When PET stage was compared with histopathologic stage, the disease in 72 (86%) patients was accurately staged with PET, understaged in two (2%), and overstaged in 10 (12%). The overall sensitivity, specificity, and positive and negative predictive values for PET of regional lymph nodal metastases were 82%, 86%, 47%, and 97%, respectively. CONCLUSION: 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 these patients can proceed directly to thoracotomy.

Correlation of tumor size and survival in patients with stage IA non-small cell lung cancer.

OBJECTIVE: The purpose of this study was to determine the relationship between tumor size and survival in patients with stage IA non-small cell lung cancer (non-small cell lung cancer; ie, lesions < 3 cm). METHOD: Five hundred ten patients with pathologic stage IA (T1N0M0) non-small cell lung cancer were identified from our tumor registry over an 18-year period (from 1981 to 1999). There were 285 men and 225 women, with a mean age of 63 years (range, 31 to 90 years). The Cox proportional model was used to examine the effect on survival. Tumor size was incorporated into the model as a linear effect and as categorical variables. The Kaplan-Meier product limit estimator was used to graphically display the relationship between the tumor size and survival. RESULTS: The Cox proportional hazards model did not show a statistically significant relationship between tumor size and survival (p = 0.701) as a linear effect. Tumor size was then categorized into quartiles, and again there was no statistically significant difference in survival between groups (p = 0.597). Tumor size was also categorized into deciles, and there was no statistical relationship between tumor size and survival (p = 0.674). CONCLUSIONS: This study confirms stratifying patients with stage IA non-small cell lung cancer in the same TNM classification, given no apparent difference in survival. Unfortunately, these data caution that improved small nodule detection with screening CT may not significantly improve lung cancer mortality. The appropriate prospective randomized trial appears warranted.

Lung cancer and positron emission tomography with fluorodeoxyglucose.

Over the past years, positron emission tomography (PET) with fluoro-2-deoxy-D-glucose (FDG) has emerged as an important imaging modality. In the thorax, FDG-PET has been shown to differentiate benign from malignant pulmonary lesions and stage lung cancer. Preliminary studies have shown its usefulness in assessing tumor recurrence, and assisting in radiotherapy planning. FDG-PET is often more accurate than conventional imaging studies, and has been proven to be cost-effective in evaluating lung cancer patients. This review will discuss the current applications of FDG-PET as compared with conventional imaging in diagnosing, staging, and following patients with lung cancer.

Imaging bronchogenic carcinoma.

Imaging plays an integral role in diagnosing, staging, and following patients with lung cancer. Most lung tumors are detected on chest radiographs, but unfortunately, the majority of patients have advanced stage disease at presentation. There is a wide spectrum of radiologic manifestations of lung cancer, and recognition of these findings is essential for patient management. As we continue to understand more about tumor biology, new imaging techniques should emerge and have the potential to significantly improve our diagnostic capabilities.

Management of malignant pleural effusions and pneumothorax.

Pneumothorax may occur spontaneously or result from underlying lung disease or as a complication of interventional thoracic procedures. Percutaneous catheter placement enables safe and effective drainage of pneumothoraces with rapid relief of symptoms and restoration of vital capacity and oxygenation.

Prognostic value of thoracic FDG PET imaging after treatment for non-small cell lung cancer.

OBJECTIVE: We determined the prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for patients with treated lung cancer. MATERIALS AND METHODS: We examined patients who underwent FDG PET after first-line treatment for non-small cell lung cancer. FDG PET results were correlated with survival rates to determine whether FDG PET findings were predictive of outcomes. RESULTS: After initial therapy, 113 patients with non-small cell lung cancer underwent FDG PET. One hundred patients had positive FDG PET results and a median survival of 12 months (95% confidence interval, 9.2-15.4). Thirteen patients had negative FDG PET results, and 11 (85%) of these patients are still living at a median follow-up of 34 months. The difference in survival for patients with positive and negative FDG PET results was statistically significant (p = 0.002). CONCLUSION: FDG PET has prognostic value and strongly correlates with survival rates of patients with treated 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 therapeutic treatments.

Lung nodule enhancement at CT: multicenter study.

PURPOSE: To test the hypothesis that absence of statistically significant lung nodule enhancement (< or =15 HU) at computed tomography (CT) is strongly predictive of benignity. MATERIALS AND METHODS: Five hundred fifty lung nodules were studied. Of these, 356 met all entrance criteria and had a diagnosis. On nonenhanced, thin-section CT scans, the nodules were solid, 5-40 mm in diameter, relatively spherical, homogeneous, and without calcification or fat. All patients were examined with 3-mm-collimation CT before and after intravenous injection of contrast material. CT scans through the nodule were obtained at 1, 2, 3, and 4 minutes after the onset of injection. Peak net nodule enhancement and time-attenuation curves were analyzed. Seven centers participated. RESULTS: The prevalence of malignancy was 48% (171 of 356 nodules). Malignant neoplasms enhanced (median, 38.1 HU; range, 14.0-165.3 HU) significantly more than granulomas and benign neoplasms (median, 10.0 HU; range, -20.0 to 96.0 HU; P < .001). With 15 HU as the threshold, the sensitivity was 98% (167 of 171 malignant nodules), the specificity was 58% (107 of 185 benign nodules), and the accuracy was 77% (274 of 356 nodules). CONCLUSION: Absence of significant lung nodule enhancement (< or = 15 HU) at CT is strongly predictive of benignity.

Lung nodules: dual-kilovolt peak analysis with CT--multicenter study.

PURPOSE: To test the following hypothesis: The greater the increase in the mean computed tomographic (CT) number of a radiologically indeterminate lung nodule from the CT number on a 140-kVp CT image to that on an 80-kVp CT image, the more likely the nodule is benign (ie, contains calcium). MATERIALS AND METHODS: Two hundred forty indeterminate lung nodules were prospectively studied at four institutions: Mayo Clinic Scottsdale, Ariz (n = 160); Mayo Clinic Rochester, Minn (n = 50); Shiga Health Insurance Hospital, Otsu, Japan (n = 25); and Duke University Medical Center, Durham, NC (n = 5). Of the 240 nodules, 157 met the entrance criteria for this study and had a diagnosis. All nodules included were solid, 5-40-mm diameter, relatively spherical, homogeneous, and without visible evidence of calcification or fat. Each nodule was evaluated by using 3-mm-collimation, nonenhanced CT scans with both 140- and 80-kVp x-ray beams. RESULTS: There were 86 (55%) benign and 71 (45%) malignant nodules. The median increase in the nodule mean CT number from the CT number on 140-kVp images to that on 80-kVp images was 2 HU for benign nodules and 3 HU for malignant nodules. This difference was not statistically significant. The area under the receiver operating characteristic curve was 0.505. CONCLUSION: Dual-kilovolt peak analysis with current CT technology does not appear to be helpful in the identification of benign lung nodules.