Thoracic Imaging 2003 - Society of Thoracic Radiology

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Assessing Growth of Indeterminate Nodules Helen T. Winer-Muram, M.D. Indiana University Why measure growth? Indeterminate lung nodules have been considered to be benign if they 1) have a “benign” pattern of calcification or 2) do not grow over a period of two years. Controversy has arisen, however, about these indicators. Gurney had four radiologists review radiographic features of 44 malignant nodules and showed that 5% had a “benign” pattern of growth. Yankelevitz et al. have used data from early studies of radiographic nodule growth to calculate that the predictive value of no growth is only 65%. Measurement of nodule growth rates offer a way to separate benign from malignant nodules. Chest radiographic data have shown that most malignant nodules double in volume in between 20 and 400 days. Nodules that grow more quickly are more likely to be infectious, while those that grow more slowly are likely to be benign nodules (e.g., hamartomas, granulomas) (Nathan). Moreover, the advent of lung cancer screening makes the determination of nodule growth rates even more important. Screening may preferentially detect slow-growing nodules that may not be lethal. Patients with fast-growing nodules may not be curable even if the nodules are detected when they are small. In addition, the rate of growth of the lung cancer might be correlated with disease-specific mortality. How do tumors grow? For growth rates to be used for clinical decision making, it is best that the tumor growth is linear. This fact has been suggested by past radiological studies. From chest radiography (41 cases) it has been shown that tumors have a linear increase in volume over time (Garland, 1963). Once the growth levels off, (upper horizontal asymptote) there is a lethal burden of tumor and the patient is near death. That is generally at about 40 doubling times. As radiologists view nodules, we get the misconception that tumors grow faster as they enlarge. The same percent growth of a large diameter is more noticable than that of a smaller diameter. Why “watch” a nodule and not immediately get tissue? Many CT-detected indeterminate nodules are too small (< 1 cm diameter) for fine needle aspiration biopsy, and some larger nodules are in anatomic locations that make biopsy difficult. In areas endemic for fungal disease, we cannot biopsy all of the indeterminate nodules that are discovered with CT. Lung cancer screening programs in the Midwest have shown that 50% of patients have indeterminate nodules, most of which are benign at biopsy. Currently 20% to 40% of all resected nodules are benign. Swenson et al. have proposed including an enhanced CT study to aid in discriminating benign from malignant nodules; nodule enhancement of < 20 HU with CT (4 scans at 1 minute intervals after contrast injection) has a negative predictive value of 98%. To use nodule growth rate as a way to distinguish between benign and malignant lesions, it must demonstrated that a clinically acceptable delay between initial and followup CT scans is usually sufficient to show growth. “Watchful waiting” even for one month is controversial, even though no one has shown that such a delay would have deleterious effects. In addition, measurements to assess for growth must be reproducible. Several studies using different methods have been reported. Radiography studies – diameter method (For spherical tumors a 25% increase in diameter ~ a 100% increase in volume.) Usada et al measured the doubling times (DTs) of lung cancer nodules in 174 patients. The DTs ranged from 30 to 1077 days; 7% of patients had DTs > 500 days. In that study the DT was an independent predictor of mortality. In a retrospective review of 300 cases, the DTs for adenocarcinoma s were 185 days, squamous cell carcinomas were 90 days, and small cell carcinomas were 65 days (Friberg). Aoki et al. described DTs vary that ranged from 42 to 1486 days in 27 cases of bronchioloalveolar cell carcinomas. Hopper found the interobserver variability to be < 15%, with a minimal detectable change of 3 to 5 mm (Hopper). CT studies – diameter method Yankelevitz et al. (1999) have calculated that the minimal measurable change in diameter is 0.3 mm or one pixel Even a nodule of 1 cm diameter with a 180 day DT will have measurable change in diameter if the interval between CT scans is at least 28 days. In a screening study, Hasegawa et al. measured 82 cancers (most adenocarcinoma) and found 27 had DTs > 450 days (33%) and 12 had DTs > 730 days (15%). They pointed out that use of a screening population may lead to a bias toward slow-growing tumors Harris measured phantoms using different window/level settings. Measurements were highly accurate with lung window settings and inaccurate with soft tissue settings. This is evidence that serial measurements should be done with the same window/level settings. CT studies – maximum cross sectional area method Yankelevitz measured the maximal cross-sectional areas of 9 malignant nodules. All had diameters < 10 mm and all had projected change in area of > 18 % in 30 days. The DTs were all < 124 days. (range 53-124 days, median 75 days) For repeated area measurements of small tumors, Staron found the intraobserver coefficient of variation to be only 4-7% for an object of cross-sectional area of 705 mm 2 , a typical size for a stage I lung tumor. CT studies – volume method An exciting new development is that of volumetric measurement of nodules. Because volume varies with the cube of the diameter, for a given time period the percent change in volume is greater than the percent change in the diameter. If volume and diameter measurements are equally precise, volume changes should be detectable earlier than diameter changes. As cross- 221 WEDNESDAY
WEDNESDAY 222 sectional area varies with the square of the diameter, volume change should be detectable more quickly than area change as well. Tiitola showed excellent interobserver agreement (k = 0.78) for manual volume measurements of irregular phantoms (8.7 cm 3 to 31.6 cm 3 ) Intraobserver agreement was even better. Yankelevitz et al. measured volumes of spherical phantoms (3- 11 mm diameter) and showed 465 days (22%). There was considerable overlap between histologic subtypes. We continue to accrue patients and refine our methodology, and continue to find a wide range in DTs and a large number of patients with very long DTs. Advantages of volume measurement As previously mentioned, volume change should be detectable more quickly than area or diameter change. In addition, volume measurement accounts for growth in the z-axis, which may be asymmetric compared with that in the x-y plane. One also does not need to match images as one does for diameters and cross sectional areas. Problems of volume measurement The major source of error in volume measurement is the partial volume effect. The magnitude of this source of error varies inversely with the size of nodule (larger is better), directly with section width (smaller is better), and directly with the orientation of the nodule (long axis along z-axis is better). We have been developing methods to reduce this error with some success. Patient motion (breathing and cardiac) decreases measurement precision and is noticeable in up to 25% of studies. Misregistration may also lead to errors. In addition, errors common to all measurement methods include the inclusion of adjacent structures, or adjacent areas of atelectasis or pneumonitis, in the dimensions of the tumor. For precise manual measurement of volumes on serial CT scans - KEEP EVERYTHING THE SAME! Same CT scanner Same scan parameters (kVp and mA) Same pitch and section width Same viewing station and window/level settings Same field-of-view (FOV) – this may be less important Same radiologist if possible The introduction of multislice scanners and automated measurement techniques will reduce some of the sources of error in volume measurement because reproducibility will increase, and patient motion will become less noticeable. In addition, narrower section widths will reduce the partial volume effect. However, separating tumor from other structures (segmentation) will still be an issue, and appropriate window/level setting must be chosen (threshold selection). Final thought If a 1 cm 3 nodule = 32 generations = 10 9 cells, and we assume that the rate of growth is linear, an adenocarcinoma will grow for 22.5 years to become1 cm 3 and a squamous cell carcinoma will grow for 7.8 years to become 1 cm 3 . It will be interesting to see if lung cancer screening can actually reduce disease specific mortality. REFERENCES: Yankelevitz DF, Henschke CI. Does 2-year stability imply that pulmonary nodules are benign? AJR 1997;168:325-328 Good CA, Wilson TW. The solitary circumscribed pulmonary nodule: study of seven hundred fifty cases encountered roentgenologically in a period of three and one half years. JAMA 1958;166:210 215 Lillington GA. Benign tumors. In Murray JF, Nadel JA. eds Textbook of respiratory medicine 2nd ed. Philadelphia Saunders 1995;1622-1630 Midthun DE, Swenson SJ, Jett JR. Clinical strategies for solitary pulmonary nodule. Annu Rev Med 1992;43:195-208 Lillington GA Caskey CI Evaluation and management of solitary and multiple pulmonary nodules. Clin Chest Med 1993;14:111- 119 Gurney JW, Lyddon DM, McKaay JA. Determining the likelihood of malignancy in solitary pulmonary nodules with Bayesian analysis Part II. Application Radiology 1993;186:415-422 Friberg S, Mattson S. On the growth rates of human malignant tumors: Implications for medical decision making. J of Surgical Oncology 1997;65:284-297. Garland LH, Coulson W, Wollin E. The rate of growth and apparent duration of untreated primary bronchial carcinoma. Cancer 1963;16:694-707 Nathan MH, Collins VP, Adams RA. Differentiation of benign and malignant pulmonary nodules by growth rate. Radiology 1962;79:221-231 Cummings SR, Lillington GA, Richard RJ. Managing solitary pulmonary nodules: the choice of strategy is a “close call.” Am Rev Resp Dis 1986;134:453-460 Swenson SJ, Brown LR, Colby TV, Weaver AL, Midthun DE. Lung nodule enhancement at CT: Prospective findings. Radiology 1996;201:447-455 Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR 2000;174:763-768 Staron RB, Ford E. Computed tomographic volumetric calculation reproducibility. Invest Radiol 1986;21:272-274 Harris KM Adams DC Lloyd DCF, Harvey DJ. The effect on apparent size of simulated pulmonary nodules of using three standard CT window settings. Clin Radiology 1993;47: 241-244 Usada K, Saito Y, Sagawa M, et al. Tumor doubling time and prognostic assessment of patients with primary lung cancer. Cancer 1994;74:2239-44 Yankelevitz DF, Gupta R, Zhao B, Henschke CI. Small pulmonary nodules: Evaluation with repeat CT – preliminary experience. Radiology 1999;212:561-566 Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening Br J Radiol 2000;73:1252-1259 Yankelevitz DF, Reeves AP, Kostis WJ, Zhao B, Henschke CL. Small pulmonary nodules volumetrically determined growth rates based on CT evaluation. Radiology 2000;217:251-256 Tiitola M, Krivisaari L, Tervaahaartiala P, Palomaaki M, Kivisaari RP, Mankinen P, Vehmas T. Estimation or quantification of tumor volume? CT study on irregular phantoms. Acta Radiologica 2001;42:101-105
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The Society of Thoracic Radiology T
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Dear Friends, Welcome to Miami Beac
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Continuing Medical Education Credit
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Warren B. Gefter, MD University of
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Ernest M. Scalzetti, MD SUNY Upstat
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Registration Hours Saturday, March
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Program Committee Ella A. Kazerooni
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Small Airway Disease Americana 3 Mo
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Benjamin Felson Memorial Lecture Am
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Session 2-B Concurrent Session Clin
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Workshops (choose 1) 1:00 - 1:45 D1
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Sunday
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March 2, 2003 General Session Sunda
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SUNDAY 46 One type of direct-readou
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CT-PET Imaging Suzanne Aquino, M.D.
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SUNDAY 58 an accompanying decreased
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SUNDAY 60 Radiofrequency Ablation i
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SUNDAY 62 17. Sewell PE, Vance RB.
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SUNDAY 64 cal ventilation will be r
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SUNDAY 66 radiologic, and histopath
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SUNDAY 68 application. The untreate
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SUNDAY 70 The Expanded Spectrum of
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SUNDAY 72 Hypersensitivity Pneumoni
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SUNDAY 74 Small Airway Diseases Mic
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SUNDAY 76 The “Head-cheese Sign
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SUNDAY 78 “Holes” in the Lung:
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SUNDAY 80 Pleural Effusions Gerald
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SUNDAY 82 Asbestos Related Pleural
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SUNDAY 84 Other Pleural Neoplasms S
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SUNDAY 86 Image-Guided Therapy of M
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Notes 88
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March 3, 2003 General Session 7:00
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Cardiac MRI: Established Indication
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Cardiac MRI: New Developments Gauth
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5. The volume of contrast medium re
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Acute Aortic Syndrome Ernest M. Sca
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as well as separation of the cusps
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Pulmonary Veins: Imaging for Radiof
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Imaging of Cardiopulmonary Support
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plied to the hollow fibers by an ex
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swelling of the entire leg, calf sw
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Multi-channel Pulmonary CTA: New Te
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terminate scintigrams, CT correctly
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CT Strucural and Functional Imaging
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curves (TDCs) are generated by manu
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7. Crawford T, Yoon C, Wolfson K, e
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80. Fleischmann D, Rubin GD, Bankie
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127 MONDAY
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129 MONDAY
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REFERENCES Bergin CJ, Rios G, King
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Notes 134
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March 4, 2003 General Session 7:00
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Adult Manifestations of Congenital
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will usually display the limbs of t
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Imaging of the Pericardium Paul L.
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Cardiomyopathy Martin J. Lipton, M.
Page 113 and 114: TUESDAY 150 Nuclear Cardiology Upda
Page 115 and 116: TUESDAY 152 ties. The predominant 1
Page 117 and 118: TUESDAY 154 Imaging protocols: Util
Page 119 and 120: Manpower Shortage in Radiology: Sol
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Page 127 and 128: NIBIB Update for Thoracic Radiology
Page 129 and 130: vertically along the right atrium t
Page 131 and 132: Multidetector Pediatric Chest CT: P
Page 133 and 134: The Spectrum of Pulmonary Infection
Page 135 and 136: Immune deficiency occurs frequently
Page 137 and 138: TUESDAY 180 The Internet and the Pr
Page 139 and 140: TUESDAY 182 Workshop A1: Lymphoma:
Page 141 and 142: TUESDAY 184 Digital Images: Camera
Page 143 and 144: TUESDAY 186 Analysis of Mediastinal
Page 145 and 146: Unusual Manifestations of Lung Canc
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Page 149 and 150: March 5, 2003 General Session Wedne
Page 151 and 152: WEDNESDAY 208 principle is that “
Page 153 and 154: WEDNESDAY 210 years and a current o
Page 155 and 156: WEDNESDAY 212 lesions generally mim
Page 157 and 158: WEDNESDAY 214 capable of studying t
Page 159 and 160: WEDNESDAY 216 Small T1 Lung Cancer:
Page 161 and 162: WEDNESDAY 218 REFERENCES Seely JM,
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Page 167 and 168: WEDNESDAY 224 Lung Cancer Staging A
Page 169 and 170: Metastatic Disease to Lung Gordon L
Page 171 and 172: Thoracic Metastates from Osteosarco
Page 173 and 174: STR tutorial: Use of MD CT reconstr
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Page 177 and 178: WEDNESDAY 236 Pulmonary Arterial Hy
Page 179 and 180: WEDNESDAY 238 pathological process,
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Page 183 and 184: THURSDAY 250 Pulmonary Tuberculosis
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Page 189 and 190: THURSDAY 256 Viral Infection on HRC
Page 191 and 192: THURSDAY 258 Imaging of Coccidioido
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Page 195 and 196: THURSDAY 262 Inflammatory Diseases
Page 197 and 198: Virtual Endoscopy in the Thorax: Pr
Page 199 and 200: Notes 269 THURSDAY
Page 201: SECOND LEVEL THIRD LEVEL
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