Patients with lung cancer are at risk for adrenal metastasis.

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1 MRI as an Alternative to CT-Guided Biopsy of Adrenal Masses in Patients With Lung Cancer Lawrence H. Schwartz, MD, Michelle S. Ginsberg, MD, Michael E. Burt, MD, PhD,* Karen T. Brown, MD, George I. Getrajdman, MD, and David M. Panicek, MD Department of Radiology and Division of Thoracic Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York Background. This study was performed to assess chemical shift magnetic resonance imaging (CSMRI) for characterizing adrenal masses in patients with lung cancer, and to compare charges associated with two algorithms for assessing adrenal masses in these patients. Methods. Forty-two patients with lung cancer underwent both CSMRI (using in-phase and opposed-phase gradient echo images) and computed tomography-guided percutaneous biopsy of adrenal masses. Adrenal-tospleen signal intensity ratios on the opposed-phase images were correlated with histopathologic results. The normalized charges for two algorithms were compared. In algorithm A, computed tomography-guided biopsy is used first to evaluate an adrenal mass; in algorithm B, CSMRI is used first, followed by computed tomographyguided biopsy only if CSMRI findings are not diagnostic of adenoma. Results. Biopsy showed 24 (57%) adrenal adenomas and 18 (43%) metastases. Chemical shift magnetic resonance imaging was 96% sensitive for adenoma and 100% specific. The average normalized charges associated with algorithm A were $1,905 per patient versus $1,890 with algorithm B. Conclusions. Initial use of CSMRI in evaluating an adrenal mass in lung cancer patients can obviate biopsy in 55% of patients, and its charges are similar to those for performing computed tomography-guided biopsy in all patients. (Ann Thorac Surg 1998;65:193 7) 1998 by The Society of Thoracic Surgeons Patients with lung cancer are at risk for adrenal metastasis. Unfortunately, other types of adrenal masses are present in a substantial proportion of patients (2% to 9%) [1]; these usually represent adrenocortical adenomas, but other benign adrenal lesions occur, including myelolipoma, cyst, pheochromocytoma, and hematoma. The latter four entities usually can be differentiated from adenoma or metastasis on the basis of computed tomography (CT) or clinical findings or both, but differentiation between adenoma and metastasis is often difficult. Because the presence of adrenal metastasis in a patient with lung cancer can have profound therapeutic implications, a test that could reliably distinguish adrenal metastasis and adrenal adenoma would be most helpful. Standard CT-guided percutaneous biopsy of adrenal masses is an accurate, albeit invasive, method for showing the cause of an adrenal mass. However, sampling errors can occur, and the procedure may cause complications [2]. Chemical shift magnetic resonance imaging (CSMRI), performed during a breath-hold, recently has been shown to be a fast, highly specific and highly sensitive method for the diagnosis of adrenocortical adenoma [3 7], in distinction to the less successful earlier attempts using magnetic resonance imaging (MRI) signal Accepted for publication July 9, Address reprint requests to Dr Schwartz, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY ( schwartl@mskcc.org) * Doctor Michael E. Burt passed away on October 4, analysis on conventional T1-weighted and T2-weighted spin-echo images [8]. This fast MRI technique shows dark signal from adrenocortical adenomas on opposedphase gradient echo images because they typically contain lipid, in contrast to adrenal metastases, which do not [3 7]. To provide information on the appropriate use of these two radiologic methods, we compared the charges associated with two algorithms, using normalized charges [9, 10] incurred by patients from our institution. In algorithm A, CT-guided biopsy is used as the first method to evaluate an adrenal mass; in algorithm B, CSMRI is the first method, followed by CT-guided biopsy only in patients whose CSMRI findings are not diagnostic of adenoma. Material and Methods Patients Forty-two patients with newly diagnosed lung cancer were referred for CSMRI of an adrenal mass before CT-guided percutaneous biopsy of that mass between May 1993 and September The adrenal masses were discovered on initial staging CT scans. Twenty-five patients were men and 17 were women (mean age, 67 years; range, 41 to 83 years). Findings in some of these patients have been reported previously [11]. The histologic types of the primary lung tumors could be determined in 31 cases: adenocarcinoma (n 14), non small cell (not otherwise specified) (n 8), squa by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (97)

2 194 SCHWARTZ ET AL Ann Thorac Surg MRI AND CT-GUIDED BIOPSY OF ADRENAL MASSES 1998;65:193 7 mous (n 5), large cell (n 3), and adenosquamous (n 1). The types in 8 of the remaining patients could not be determined because patients were seen in consultation at our institution and were then lost to follow-up; in 3 others, the information cannot be obtained. Ten of the 31 patients had stage I, 8 had stage IIIA, and 13 had stage IIIB disease. Magnetic Resonance Imaging Magnetic resonance imaging was performed on a Signa 1.5-Tesla scanner (software versions 4.7, 5.3, and 5.4) (General Electric Medical Systems, Milwaukee, WI) within 7 days before the CT-guided biopsy. Patients were scanned supine using the body coil. Chemical shift MRI was performed with a gradient echo pulse sequence (repetition time 86 milliseconds, echo time 2.1 to 2.3 milliseconds, 90 degrees flip angle) to produce opposedphase images, using 8-mm slice thickness, 2-mm interslice gap, two signals acquired, and a matrix. Twelve axial slices were obtained during a 23-second breath-hold. Conventional spin-echo (in-phase) T1- weighted (repetition time 500 milliseconds, echo time 16 milliseconds) or in-phase gradient echo (repetition time 86 milliseconds, echo time 4.2 milliseconds, 90 degrees flip angle) images also were obtained in 13 and 29 patients, respectively. Adrenal-to-spleen signal intensity ratios were calculated on the opposed-phase gradient echo images. Signal intensity measurements on the MRI images were derived from the mean of three regions of interest in the adrenal mass and in the spleen. Computed Tomography-Guided Biopsy Needle biopsies were performed as an outpatient procedure using a 1200SX CT scanner (Picker International, Cleveland, OH) or 9800 Advantage CT scanner (GE Medical) for guidance. Patients were given conscious sedation, and their vital signs, cardiac rhythm, and pulse oximetry were monitored continuously. The adrenal mass was localized with 10-mm axial sections, followed by 5-mm sections through the mass. A 22-gauge needle was advanced into the mass, with needle position documented by repeat axial scan. Smears made of the specimen obtained were reviewed immediately for adequacy by an on-site cytotechnologist. Additional passes of the biopsy needle were made until an adequate specimen was obtained. After the biopsy, CT sections were obtained to check for hemorrhage. If lung was traversed during the biopsy, a single CT section through the chest was obtained, as well as a chest radiograph 2 hours after the biopsy, to check for the presence of pneumothorax. Analysis of Charges To compare the relative charges of the two algorithms, and to make the results of the analysis independent of the specific charges at our institution, we normalized the charges that were billed in our hospital (based on the associated procedure codes) using national relative value scale (RVS) charges [9] and national conversion factors [10] used in the United States. The normalized charges Fig 1. Comparison of adrenal-to-spleen signal intensity ratios at chemical shift magnetic resonance imaging for benign adrenal lesions (adrenocortical adenomas) versus malignant adrenal lesions (metastases) from lung cancer. (combining all technical and professional charges that were actually incurred) were evaluated for MRI and for CT-guided biopsy. The latter charges included the cost of CT-guided biopsy itself, pathologic examination and staining of specimens, and diagnosis and treatment of any associated complications that occurred. A decision analysis was performed to compare the relative costs incurred by algorithm A (ie, CT-guided adrenal biopsy performed in every patient) versus algorithm B (ie, CSMRI performed in all patients, followed by CT-guided adrenal biopsy only in those patients with CSMRI findings not diagnostic of adrenocortical adenoma). Results Magnetic Resonance Imaging Magnetic resonance images were of diagnostic quality in all 42 patients. The mean size of benign adrenal masses was 1.9 cm (range, 1.0 to 4.0 cm); the mean size of malignant adrenal masses was 4.3 cm (range, 1.0 to 7.6 cm). The adrenal-to-spleen signal intensity ratio on opposed-phase gradient echo images for adrenocortical adenomas was , versus for adrenal metastases (p 0.001) (Fig 1). The sensitivity and specificity of the ratio for the diagnosis of adrenocortical adenoma at CSMRI (using a cutoff value of 0.55, as reported previously [6]) were 96% and 100%, respectively. Computed Tomography-Guided Biopsy Computed tomography-guided biopsy yielded specimens adequate for cytologic analysis in all cases. Eigh-

3 Ann Thorac Surg SCHWARTZ ET AL 1998;65:193 7 MRI AND CT-GUIDED BIOPSY OF ADRENAL MASSES 195 Fig 2. Expected distribution of 100 patients presenting with lung cancer and an adrenal mass, based on 55% prevalence of adrenocortical adenoma in this population, and sensitivity of 96% and specificity of 100% for diagnosing adrenocortical adenoma with chemical shift magnetic resonance imaging (CSMRI). (CT computed tomography.) teen (43%) of the adrenal masses were shown by CTguided biopsy to be metastases, and 24 (57%) masses yielded benign adrenal cells but no malignant cells at CT-guided biopsy, consistent with adrenocortical adenoma. The only complication encountered in this study was pneumothorax in 3 patients. Each of the 3 required additional follow-up chest radiographs, but no chest tube placement. No patient required hospitalization as a result of the biopsy procedure. Analysis of Charges The average CT-guided biopsy charge was $1,905 per patient, including all the technical and professional charges for CT-guided biopsy itself ($1,458), pathologic examination of the biopsy specimens ($157 to $479), and miscellaneous charges, including diagnosis and treatment of the associated complications (pneumothorax in 3 patients, not requiring chest tube placement, $0 to $112). The normalized MRI charge was $1,032 per patient, including both the technical and professional charges. If all patients underwent CT-guided biopsy without MRI (algorithm A), the average total charge would be $1,905 per patient. Given the observed 57% prevalence of adrenocortical adenomas, and 96% sensitivity and 100% specificity of CSMRI for the diagnosis of adrenocortical adenoma, CSMRI would be expected to correctly diagnose adrenocortical adenoma in 55% (Fig 2). If subsequent confirmation with biopsy were required only in those patients in whom CSMRI findings were not diagnostic of adrenocortical adenoma (algorithm B), then 45% of patients with adrenal masses would also need to undergo CT-guided adrenal biopsy after CSMRI. Thus, 100% of the group would undergo MRI (charges: $1,032), and 45% also would require CT-guided biopsy (charges: $1,905), resulting in an average total charge of $1,032 (45% $1,905) $1,890 per patient for algorithm B. Although essentially equivalent in cost to algorithm A, algorithm B would avoid the need to perform invasive CT-guided biopsy in 55% of patients. Fig 3. Chemical shift magnetic resonance imaging scan of typical adrenal adenoma. The patient is a 54-year-old woman with poorlydifferentiated non small cell carcinoma. The 1.8-cm left adrenal adenoma (arrow) has a very dark signal because the adenoma contains both water and lipid. Comment Benign adrenal lesions, mostly representing adrenocortical adenomas, are commonly discovered at initial staging CT of patients with lung cancer. For example, Oliver and colleagues [12] found that 9.7% of 330 patients with non small cell lung cancer had an adrenal mass; 78% of those masses were potentially the only site of metastatic disease, yet fully 68% of those masses were subsequently shown to be benign. The prognosis and therapy in a given patient may be altered based on whether an adrenal mass is benign or malignant. For example, median survival in one series of patients with non small cell lung cancer and a unilateral adrenal mass was greater than 30 months for those whose masses were benign versus 9 months for those with adrenal metastases [13]. Thus, a noninvasive imaging method for determining the nature of an adrenal mass would be most helpful. The specificity of such a method must be virtually 100% to avoid the potentially disastrous misdiagnosis of a malignant tumor as being a benign lesion, given that an adrenal metastasis is generally considered a contraindication to curative resection. Adrenocortical adenomas typically contain considerably more lipid than do other adrenal neoplasms [1, 3 7, 14, 15]. A tissue that contains both lipid and water will have low (dark) signal on opposed-phase CSMRI (Figs 3, 4) because those substances have opposite signals that cancel each other out with that technique; in contrast, tissues that are composed mostly of water or fat will have intermediate or bright signal intensity (Fig 4). Adrenal metastases and adrenocortical carcinomas maintain intermediate or bright signal on opposed-phase CSMRI (Fig 5) because they typically do not contain appreciable amounts of lipid. Thus, CSMRI is able to diagnose the large majority of adrenocortical adenomas (96% in this study), with biopsy still being required to identify the infrequent adenoma that contains little or no lipid [15]. Biopsy also is usually performed to confirm the sus-

4 196 SCHWARTZ ET AL Ann Thorac Surg MRI AND CT-GUIDED BIOPSY OF ADRENAL MASSES 1998;65:193 7 Fig 4. Chemical composition and chemical shift (fast) magnetic resonance imaging (MRI) findings in adrenal adenomas, metastases, and lipomas. pected diagnosis of metastasis, with subsequent adrenalectomy if results of CT-guided biopsy are indeterminate [13]. Chemical shift MRI is now widely available with routine software platforms on current MRI systems. Using gradient echo pulse sequences, in-phase and opposedphase images can be obtained by selecting appropriate echo times, which depend on the magnetic field strength of the MR scanner used; for example, at 1.5 Tesla, a gradient echo image obtained with an echo time of 2.1 milliseconds will be an opposed-phase image, and a gradient echo image obtained with an echo time of 4.2 milliseconds will be in-phase. (In distinction, conventional spin-echo and fast spin-echo pulse sequences always result in in-phase images, regardless of the echo time selected.) The relative cost-effectiveness of an imaging technique or algorithm is influenced by the prevalence of adenomas and metastases in the patient group being examined, as Fig 5. Chemical shift magnetic resonance imaging scan of typical adrenal metastasis from non small cell lung cancer. The patient is a 70-year-old woman with adenocarcinoma. The 4-cm left adrenal metastasis (arrow) has intermediate signal (similar to that of spleen) because no appreciable amount of lipid is present to cancel the signal from water within the metastasis. well as the charges for each procedure at a particular facility. In our study group of patients with adrenal masses, the prevalence of adenomas was 57%, and that of metastases was 43%; the resulting mean costs for the two algorithms were similar ($1,905 for algorithm A, $1,890 for algorithm B). Using the higher prevalence (68%) noted in the study by Oliver and colleagues [12], 35 patients would require biopsy, and 65 would have their adrenocortical adenoma diagnosed by MRI alone. The resulting mean charges would be $1,905 for algorithm A and $1,699 for algorithm B, emphasizing that CSMRI becomes more cost-effective as the prevalence of adrenal adenoma in a population increases. Also, as CSMRI is performed during 20- to 30-second breath-holds, it might be possible to perform a focused examination of the adrenal glands at a reduced charge, thereby further improving the costeffectiveness of algorithm B versus algorithm A. The results of this study are similar to those we found in a group of 54 patients with a variety of malignancies [11]; that group included 37 of the lung cancer patients from this study. Further studies need to be performed with larger numbers of cancer patients stratified by primary tumor type to determine the appropriate roles of CSMRI and CT-guided percutaneous biopsy in evaluating adrenal masses. Because of sampling error, percutaneous biopsy occasionally can yield false-positive diagnoses of adrenocortical adenoma (ie, false-negative diagnosis of malignancy) [2]; thus, biopsy does not represent a perfect standard of reference in our study. As we did not obtain surgical biopsy proof or radiologic follow-up of all the masses, it is theoretically possible that a small percentage of adrenocortical adenomas diagnosed at CT-guided biopsy were actually metastases. Also, adrenocortical adenoma and primary adrenal carcinoma can be difficult to distinguish at pathologic examination of a needle biopsy specimen, which could have resulted in false-positive or false-negative diagnoses of adrenocortical adenoma at CSMRI in this study. Our charge analysis does not attempt to analyze the effects of different patients preferences for various procedures. Some patients prefer the certainty provided by a tissue diagnosis, and might not trust a CSMRI diagnosis of adrenocortical adenoma. Moreover, our analysis did not assess actual costs, but used normalized charges as an indicator of costs [9, 10, 16]. Some patients are unable to undergo MRI because they are claustrophobic or have contraindications, such as cardiac pacemakers, intracranial aneurysm clips, or metallic intraocular foreign bodies. In those patients, nonenhanced or delayed contrast-enhanced CT of the adrenals can be used to identify adrenocortical adenomas [1, 17, 18], with subsequent biopsy required only of those adrenal masses that do not have CT attenuation measurements typical of adrenocortical adenoma. Chemical shift MRI is a rapid, specific, noninvasive method for demonstrating adrenocortical adenomas. Because more than half of adrenal masses discovered during initial staging of patients with lung cancer are adrenocortical adenomas, algorithm B (which uses CSMRI as

5 Ann Thorac Surg SCHWARTZ ET AL 1998;65:193 7 MRI AND CT-GUIDED BIOPSY OF ADRENAL MASSES 197 the first test for evaluating an adrenal mass) is more cost-effective than algorithm A (in which every patient initially undergoes CT-guided biopsy). Chemical shift MRI can avert biopsy of adrenal masses in approximately half of patients with lung cancer who are found to have an adrenal mass at staging CT. References 1. McNicholas MMJ, Lee MJ, Mayo-Smith WW, et al. An imaging algorithm for the differential diagnosis of adrenal adenomas and metastases. AJR 1995;165: Silverman SG, Mueller PR, Pinkney LP, et al. Predictive value of image-guided adrenal biopsy: analysis of results of 101 biopsies. Radiology 1993;187: Mitchell DG, Crovello M, Matteucci T, et al. Benign adrenocortical masses: diagnosis with chemical shift MR imaging. Radiology 1992;185: Tsushima Y, Ishizaka H, Matsumoto M. Adrenal masses: differentiation with chemical shift, fast low-angle shot MR imaging. Radiology 1993;186: Reinig JW, Stutley JE, Leonhardt CM, et al. Differentiation of adrenal masses with MR imaging: comparison of techniques. Radiology 1994;192: Schwartz LH, Panicek DM, Koutcher JA, et al. Adrenal masses in patients with malignancy: prospective comparison of echo-planar, fast spin-echo, and chemical shift MR imaging. Radiology 1995;197: Bilbey JH, McLoughlin RF, Kurkjian PS, et al. MR imaging of adrenal masses: value of chemical-shift imaging for distinguishing adenomas from other tumors. AJR 1995;164: Burt M, Heelan RT, Coit D, et al. Prospective evaluation of unilateral adrenal masses in patients with operable non small-cell lung cancer: impact of magnetic resonance imaging. J Thorac Cardiovasc Surg 1994;107: Relative Value Studies, Inc. Relative values for physicians, vol 2. New York: McGraw-Hill Health Care Management Group, Innovation Technologies Corp. Conversion factor reports. New York: McGraw-Hill Health Care Management Group, Schwartz LH, Panicek DM, Doyle MV, et al. Comparison of two algorithms and their associated charges when evaluating adrenal masses in patients with malignancies. AJR 1997;168: Oliver TW Jr, Bernardino ME, Miller JI, et al. Isolated adrenal masses in nonsmall-cell bronchogenic cancer. Radiology 1984;153: Ettinghausen SE, Burt ME. Prospective evaluation of unilateral adrenal masses in patients with operable non-small-cell lung cancer. J Clin Oncol 1991;9: Schlund JF, Kenney PJ, Brown ED, et al. Adrenocortical carcinoma: MR imaging appearance with current techniques. J Magn Reson Imag 1995;5: Korobkin M, Giordano TJ, Brodeur FJ, et al. Adrenal adenomas: relationship between histologic lipid and CT and MR findings. Radiology 1996;200: Eisenberg JM. Clinical economics: a guide to the economic analysis of clinical practices. JAMA 1989;262: Outwater EK, Siegelman ES, Huang AB, Birnbaum BA. Adrenal masses: correlation between CT attenuation value and chemical shift ratio at MR imaging with in-phase and opposed-phase sequences. Radiology 1996;200: Boland GW, Hahn PF, Peña C, Mueller PR. Adrenal masses: characterization with delayed contrast-enhanced CT. Radiology 1997;202:693 6.