Bradley S. Sabloff

Interobserver and Intraobserver Variability in Measurement of Non–Small-Cell Carcinoma Lung Lesions: Implications for Assessment of Tumor Response

PURPOSE Response of solid malignancies to therapy is usually determined by serial measurements of tumor size. The purpose of our study was to assess the consistency of measurements performed by readers evaluating lung tumors. MATERIALS AND METHODS The study group was composed of 33 patients with lung tumors more than 1.5 cm. Bidimensional (BD) and unidimensional (UD) measurements were performed on computed tomography (CT) scans according to the World Health Organization (WHO) criteria and the Response Evaluation Criteria in Solid Tumors (RECIST), respectively. Measurements were performed independently by five thoracic radiologists using printed film and were repeated after 5 to 7 days. Inter- and intraobserver measurement variations were estimated through statistical modeling. RESULTS There were 40 tumors with an average size of 1.8 to 8.0 cm (mean, 4.1 cm). Analysis of variance showed a significant difference (P <.05) among readers and among the measured nodules for UD and BD measurements. Interobserver misclassification rates were more than intraobserver misclassification rates using either progressive disease or response criteria. The probability of misclassifying a tumor with the WHO criteria or RECIST was greatest with interobserver measurements when criteria for progression (43% BD, 30% UD) were used and lowest with intraobserver measurements when criteria for response (2.5% BD, 3.0% UD) were used. In addition, interobserver misclassification rates were more than intraobserver misclassification rates for both regular and irregular tumors. CONCLUSION Measurements of lung tumor size on CT scans are often inconsistent and can lead to an incorrect interpretation of tumor response. Consistency can be improved if the same reader performs serial measurements for any one patient.

Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria.

Introduction: Advances in the pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC) have demonstrated important new prognostic features that have led to changes in classification and diagnostic criteria. Methods: The literature and a set of cases were reviewed by a pathology/CT review panel of pathologists and radiologists who met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The group addressed the question of whether sufficient data exist to modify the 2004 World Health Organization (WHO) classification of adenocarcinoma and BAC to define a “minimally invasive” adenocarcinoma with BAC. The problems of diffuse and/or multicentric BAC and adenocarcinoma were evaluated. Results: The clinical concept of BAC needs to be reevaluated with careful attention to the new 2004 WHO criteria because of the major clinical implications. Existing data indicate that patients with solitary, small, peripheral BAC have a 100% 5-year survival rate. The favorable prognostic impact of the restrictive criteria for BAC is already being detected in major epidemiologic data sets such as the Surveillance Epidemiology and End-Results registry. Most lung adenocarcinomas, including those with a BAC component, are invasive and consist of a mixture of histologic patterns. Therefore, they are best classified as adenocarcinoma, mixed subtype. This applies not only to adenocarcinomas with a solitary nodule presentation but also to tumors with a diffuse/multinodular pattern. The percentage of BAC versus invasive components in lung adenocarcinomas seems to be prognostically important. However, at the present time, a consensus definition of “minimally invasive” BAC with a favorable prognosis was not recommended by the panel, so the 1999/2004 WHO criteria for BAC remain unchanged. In small biopsy specimens or cytology specimens, recognition of a BAC component is possible. However, it is not possible to exclude an invasive component. The diagnosis of BAC requires thorough histologic sampling of the tumor. Conclusion: Advances in understanding of the pathology and CT features of BAC and adenocarcinoma have led to important changes in diagnostic criteria and classification of BAC and adenocarcinoma. These criteria need to be uniformly applied by pathologists, radiologists, clinicians, and researchers. The 2004 WHO classification of adenocarcinoma is readily applicable to research studies, but attention needs to be placed on the relative proportion of the adenocarcinoma subtypes. Other recently recognized prognostic features such as size of scar, size of invasive component, or pattern of invasion also seem to be important. More work is needed to determine the most important prognostic pathologic features in lung adenocarcinoma.

Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung cancer.

Background: The authors sought to define clinicopathologic features associated with mutations of the epidermal growth factor receptor (EGFR) gene in non–small cell lung cancer (NSCLC). Methods: The authors evaluated surgically resected NSCLC tumors for EGFR (exons 18–21) and KRAS (codons 12–13) mutations and immunohistochemistry (EGFR, phosphorylated-EGFR, and HER2/Neu), and correlated results with clinical outcome and patient and disease features. After their analysis on 159 patients was completed, they selected a second cohort of Asian patients (n = 22) and compared EGFR mutation results to place of birth and immigration to the United States. Results: Of 159 patients, 14 had EGFR mutations and 18 had KRAS mutations. EGFR mutations were associated with adenocarcinoma (p = 0.002), female gender (p = 0.02), never-smoking (p < 0.0001), Asian ethnicity (p = 0.005), air bronchograms (p = 0.004), and multiple wedge resections (p = 0.03). Although statistical significance was not reached, a higher incidence of synchronous primary cancers (36% versus 17%; p = 0.09) and a smaller median tumor size (11.8 cm3 versus 24.0 cm3; p = 0.24) were seen. There was no difference in disease-free survival; however, median overall survival in patients with EGFR mutations was shorter (3.49 versus 4.29 years; p = 0.85). EGFR mutation did not correlate with immunohistochemistry. In the second cohort of 22 Asian patients, 12 (55%) had the mutation. Of interest, there was no geographic difference in incidence of EGFR mutation. Asian women with the EGFR mutation developed adenocarcinoma at an earlier age than other lung cancer patients. Conclusion: There is a distinct clinical profile for NSCLC patients with the EGFR mutation. However, this mutation does not alter disease-free survival and is likely attributable to an inherited susceptibility instead of an environmental effect.

Preoperative Chemo-Radiation-Induced Ulceration in Patients with Esophageal Cancer: A Confounding Factor in Tumor Response Assessment in Integrated Computed Tomographic-Positron Emission Tomographic Imaging

Hypothesis: Positron emission tomography can be useful in predicting response of esophageal cancer after preoperative chemo-radiation therapy (CRT). We evaluated the use of integrated computed tomography (CT)-PET among patients with esophageal cancer being considered for resection after CRT. Methods: Three reviewers blinded to clinical and pathologic staging retrospectively reviewed the CT-PET scans of patients with esophageal cancer after preoperative CRT who underwent esophagectomy. [18F]-fluoro-2-deoxy-D-glucose uptake for residual malignancy was determined by visual analysis and semi-quantitatively when standardized uptake value (SUV) was ≥4. Results: Forty-two patients underwent esophageal resection. Using visual analysis, CT-PET had a sensitivity of 47% and specificity of 58% in detecting residual malignancy. Using semi-quantitative analysis, 19 patients had a SUV ≥4 in the region of the primary esophageal tumor and were interpreted as having residual malignancy (sensitivity 43%, specificity 50%). Of these 19, six had complete pathologic response to CRT. These false-positive results, due to therapy-induced ulceration detected at endoscopy, limit the use of CT-PET alone in detecting residual malignancy. Similarly, sensitivity (25%) and specificity (73%) of endoscopy/biopsy in detecting residual malignancy were poor. However, the accuracy of CT-PET in detecting residual malignancy was improved when combined with endoscopic findings. In the absence of ulceration at endoscopy, 8 of 8 patients with SUV ≥4 after chemo-radiation had residual malignancy at surgery. Conclusions: CRT-induced ulceration results in false-positive results on CT-PET and precludes accurate detection of residual esophageal tumor. However, CT-PET in combination with endoscopy is useful in identifying patients with a high risk of residual tumor post-CRT.

Tumor cavitation during therapy with antiangiogenesis agents in patients with lung cancer

Purpose: Treatment of lung cancer patients with antiangiogenesis agents is a new promising paradigm. Tumor cavitation is frequently noted in these patients, but the clinical significance of this finding has not been fully determined. Our purposes were to evaluate the frequency, imaging characteristics, and clinical outcome of patients receiving antiangiogenesis agents who develop tumor cavitation, and correlate these findings with therapy related adverse events, especially hemoptysis. Methods: Retrospective analysis of lung cancer patients treated with antiangiogenesis agents in MD Anderson Cancer Center between June 1998 and June 2005. Clinical data were retrieved from medical records, and chest imaging findings were documented. Results: One hundred and twenty-four patients were treated in 10 different trials. All patients had advanced lung cancer and failed previous chemotherapy. Seventeen patients developed tumor cavitation during the trial (14%; median time to event, 1.8 months; range, 0.7–6.2 months), 16 patients (13%) had preexisting cavitary tumors, and 91 (73%) did not develop cavitation. Cavity formation was more common with squamous cell histology (p = 0.04) but was not associated with hemoptysis (p = 0.12), tumor location (central versus peripheral), imaging characteristics, progression-free survival (p = 0.56), or overall survival (p = 0.33). Hemoptysis was noted in five patients (median time to event, 1.3 months; range, 0.8–2.9 months). One of five patients with hemoptysis was fatal in a cavitary squamous cell tumor. Additional adverse events were hypertension, rash, and proteinuria, none associated with cavitation. Conclusion: Development of tumor cavitation is not rare in lung cancer patients treated with antiangiogenesis agents, but the clinical implications are minimal in most cases.

Role of Imaging in the Diagnosis, Staging, and Treatment of Thymoma

Thymoma is a rare mediastinal neoplasm but is the most common primary neoplasm of the anterior mediastinum. There have been only a few published reports assessing this disease. Furthermore, many of these reports are from a single institution and span several decades, which may lead to potentially misleading conclusions related to diagnosis, staging, and treatment. Computed tomography is the imaging modality of choice for evaluating thymoma and can help distinguish thymoma from other anterior mediastinal abnormalities. Tumor stage and extent of resection are the most important prognostic factors. Tumors that are encapsulated and are amenable to complete resection have a good prognosis, whereas invasive and unresectable tumors have a poor prognosis regardless of their histologic characteristics. Radiologists must be aware of the full spectrum of imaging findings of thymoma, the standard guidelines for diagnostic evaluation, and how imaging findings affect therapeutic decisions.

Multidetector CT of Solitary Pulmonary Nodules

With the increasing use of multidetector CT, small nodules are being detected more often. Although most incidentally discovered nodules are benign, usually the sequelae of pulmonary infection and malignancy, either primary or secondary, remains an important consideration in the differential diagnosis of solitary pulmonary nodules. This article reviews the role of imaging in the detection and characterization of solitary pulmonary nodules. Strategies for evaluating and managing solitary pulmonary nodules are also discussed.

Subsolid pulmonary nodules: imaging evaluation and strategic management.

Purpose of review Given the higher rate of malignancy of subsolid pulmonary nodules and the considerably lower growth rate of ground-glass nodules (GGNs), dedicated standardized guidelines for management of these nodules have been proposed, including long-term low-dose computed tomography (CT) follow-up (≥3 years). Physicians must be familiar with the strategic management of subsolid pulmonary nodules, and should be able to identify imaging features that suggest invasive adenocarcinoma requiring a more aggressive management. Recent findings Low-dose CT screening studies for early detection of lung cancer have increased our knowledge of pulmonary nodules, and in particular our understanding of the strong although imperfect correlation of the subsolid pulmonary nodules, including pure GGNs and part-solid nodules, with the spectrum of preinvasive to invasive lung adenocarcinoma. Serial CT imaging has shown stepwise progression in a subset of these nodules, characterized by increase in size and density of pure GGNs and development of a solid component, the latter usually indicating invasive adenocarcinoma. Summary There is close correlation between the CT features of subsolid nodules (SSNs) and the spectrum of lung adenocarcinoma. Standardized guidelines are suggested for management of SSNs.

CT, Positron Emission Tomography, and MRI in Staging Lung Cancer

Lung cancer is a common malignancy and remains the leading cause of cancer-related deaths in both men and women in the United States. Imaging plays an important role in the detection, diagnosis, and staging of the disease as well as in assessing response to therapy and monitoring for tumor recurrence after treatment. This article reviews the staging of the two major histologic categories of lung cancer-non-small-cell lung carcinoma (NSCLC) and small-cell lung carcinoma-and emphasizes the appropriate use of CT, MRI, and positron emission tomography imaging in patient management. Also discussed are proposed revisions of the International Association for the Study of Lung Cancers terms used to describe the extent of NSCLC in terms of the primary tumor, lymph nodes, and metastases descriptors.

Pericardial "Sleeve" Recess of Right Inferior Pulmonary Vein Mimicking Adenopathy: Computed Tomography Findings

Objective: The purpose of this study was to assess the computed tomography (CT) features of the pericardial “sleeve” recess of the right inferior pulmonary vein misinterpreted as adenopathy. Method: Six patients with fluid in the pericardial sleeve recess mistaken for adenopathy were retrospectively identified. The following CT features were assessed: location of fluid in relation to the vein, size, shape, attenuation, and mass effect on the inferior pulmonary vein. Results: The most common presentation was fluid inferior and posterior to the vein. The anterior and posterior components are typically spindle shaped, whereas the superior and inferior components are ovoid. The attenuation values of the fluid ranged from 2–32 H (mean = 13 H). None of the fluid collections exerted mass effect on the right inferior pulmonary vein. Conclusion: Although fluid in the right pulmonary venous sleeve pericardial recess can mimic adenopathy, this accumulation has a characteristic appearance, and knowledge of this normal variant is useful in preventing misinterpretation.