Use of [18F]Fluorodeoxyglucose Positron Emission Tomography in Evaluating Locally Recurrent and Metastatic Adrenocortical Carcinoma
Gavin C. Mackie, Barry L. Shulkin, Raul C. Ribeiro, Francis P. Worden, Paul G. Gauger, Rajen J. Mody, Len P. Connolly, Ghada Kunter, Carlos Rodriguez-Galindo, Jerold W. Wallis, Craig A. Hurwitz, and David E. Schteingart
Department of Radiology, Division of Nuclear Medicine (G.C.M., B.L.S.); Department of Internal Medicine, Divisions of Hematology-Oncology (F.P.W.) and Endocrinology and Metabolism (D.E.S.); Department of Surgery (P.G.G.); and Department of Pediatrics and Communicable Diseases (R.J.M.), University of Michigan Medical Center, Ann Arbor, Michigan 48109; Departments of Radiological Sciences (B.L.S.) and Hematology-Oncology (R.C.R., C.R .- G.), St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; Department of Radiology (L.P.C.), Children’s Hospital, Boston, Massachusetts 02115; Department of Pediatrics (C.A.H.), Maine Medical Center, Portland, Maine 04074; and Departments of Pediatrics (G.K.) and Radiology (J.W.W.), Washington University School of Medicine, St. Louis, Missouri 63110
Context: Adrenocortical carcinomas are uncommon, and their eval- uation by [18F]fluorodeoxyglucose positron emission tomography (FDG PET) has not been well evaluated.
Objective: The purpose of this study was to examine the potential utility of FDG PET in the detection of recurrent or metastatic adre- nocortical carcinoma.
Design: In patients with known adrenocortical carcinoma who un- derwent FDG-PET imaging for suspected recurrence or metastasis, FDG activity was compared with other imaging findings, clinical features, and the presence or absence of disease as confirmed by resection, biopsy, or clinical follow-up.
Setting: The study took place at four tertiary referral centers.
Patients or Other Participants: Twelve patients (10 females and two males, 5-71 yr of age) were evaluated.
Main Outcome Measures: The main outcome measures were FDG activity, other imaging findings, and clinical features.
Results: Abnormal FDG uptake correctly indicated tumor recurrence in 10 patients. One patient with no abnormal FDG activity had a morphological abnormality subsequently proven to be a postoperative scar. Two patients, one with very small pulmonary lesions and one with a hepatic metastasis, had false-negative findings.
Conclusions: Most adrenocortical carcinomas accumulate and re- tain FDG and thus can be visualized by PET. However, false-negative findings are possible, especially with very small lesions. (J Clin Endocrinol Metab 91: 2665-2671, 2006)
A DRENOCORTICAL CARCINOMA (ACC) is an un- common malignant neoplasm. Its estimated annual incidence in the United States is approximately 1-2 per mil- lion. Its age distribution is bimodal, with peak frequency at ages younger than 5 yr and ages 30-50 yr. The mean age at diagnosis is approximately 45 yr (1). Adrenocortical cancer is slightly more common in females than in males (59:41) (2). The etiology of ACC is not known, but smoking and oral contraceptives may be risk factors (3, 4). Additionally, there is an association with the Li-Fraumeni and Beckwith-Wiede- mann syndromes (5, 6). ACC may be biochemically active in more than 50% of patients (7).
Computed tomography (CT) or magnetic resonance (MR) imaging is used most often in the initial imaging investiga- tion of ACC. Although both modalities are useful for dis-
Abbreviations: ACC, Adrenocortical carcinoma; CT, computed to- mography; FDG, [18F]fluorodeoxyglucose; MR, magnetic resonance; PET, positron emission tomography; ROI, region of interest; SUV max/ standardized uptake value; TAP-CT, thoraco-abdominopelvic CT.
JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the en- docrine community.
tinguishing benign from malignant adrenal disease and for detecting local tumor extension, their accuracy in the detec- tion of metastatic ACC and in disease restaging during fol- low-up is less well established. Recent evidence suggests that positron emission tomography (PET) with [18F]fluorodeoxy- glucose (FDG) or [11C]metomidate may be useful for detec- tion of ACC. FDG PET is widely used for imaging of solid tumors, but because of the rarity of ACC, few studies have addressed the role of FDG PET in its assessment. There have been two studies that have specifically addressed this. A study of 10 patients with ACC consistently demonstrated abnormal metabolic activity (8). Leboulleux et al. (9) recently evaluated individual metastatic lesions in 22 patients with ACC, finding the sensitivity of PET/CT for the detection of individual lesions to be 90%. The study did have a selection bias because only patients with abnormal CT findings were included (22 of 28 patients presenting). Other adrenal FDG PET studies that included small numbers (1-3) of patients with ACC as part of an assessment of adrenal lesions in general invariably found abnormal FDG activity within ACC (10-13). We therefore investigated the utility of FDG PET in detecting recurrent and metastatic ACC.
Patients and Methods
Patients
This study was initiated at the University of Michigan Medical Center and was subsequently expanded to include three additional institutions. The study was approved by the Institutional Review Board for the Use of Human Subjects in Research and the Subcommittee for the Human Use of Radioisotopes at the University of Michigan and by the Institu- tional Review Boards of St. Jude Children’s Research Hospital. Eligible participants received FDG PET imaging to assess suspected recurrent or metastatic ACC at the four institutions between January 2000 and Sep- tember 2005. Written informed consent was obtained from patients, parents, or guardians, as appropriate.
Imaging technique
Six patients were imaged on a Siemens Biograph PET CT scanner, three patients were imaged on a Siemens ECAT HR+ scanner, one on a Siemens ECAT HR, one on a GE Discovery PET CT scanner, and one on a GE Discovery PET scanner. After an overnight or 4-h fast, patients were injected with 296-370 MBq (8-10 mCi) FDG per 1.7 m2 of body surface area. Approximately 45 min later, the patients were positioned within the PET scanner, and emission and transmission imaging were begun. Patients 1-9 and 11-12 were scanned from neck to thigh, and patient 10 was scanned from the top of the head to the bottom of the feet in two separate acquisitions. Patient 10 has undergone multiple PET scans in conjunction with clinical care for planning and evaluating the effects of radiofrequency ablation of pulmonary metastases. Images were acquired over a period of 40-60 min. Attenuation correction was performed in all patients. Attenuation correction maps were acquired either by use of a retractable germanium-68 source or by transmission imaging with CT. Images were reconstructed using an ordered subset expectation maximization (OSEM) algorithm and reviewed in multiple planes.
Image analysis
Reviewers of the images (G.C.M. and B.L.S.) were blinded to the results of other studies. Tumor uptake of FDG was assessed both qual- itatively and semiquantitatively. Organs that normally accumulate FDG were identified by visual inspection of the images. FDG activity in regions that did not normally accumulate FDG was considered abnor- mal. Uptake of tracer by the abnormal regions was analyzed qualita- tively by rating it on a scale of 0-3 in comparison with uptake by a normal region of the patient’s liver: 0, no uptake; 1, uptake less than that of the liver; 2, uptake equal to that of the liver; 3, uptake greater than that of the liver.
Semiquantitative analysis was also performed. The standardized up- take value (SUVmax) was calculated in all patients (Table 1) as follows. When an area of abnormal FDG uptake was evident on PET imaging, an elliptical region of interest (ROI) was defined over that site(s) and over a region of the liver, which served as reference organ. The elliptical ROI was defined to encompass the majority of the lesion, and the same ROI was defined in an area of normal-appearing liver, usually in the same transverse plane. The SUV max was derived from the area of greatest FDG accumulation in the ROI using software that identifies the area of max- imal FDG uptake on a pixel by pixel basis. The tumor-to-liver activity ratio was calculated as SUVmax (lesion)/SUVmax (liver). In the one pa- tient who underwent PET/CT and whose study did not show abnormal FDG uptake, the ROI was determined on the basis of the CT image.
The results of the FDG PET imaging were correlated with the findings of histology from biopsy/resection in four patients. In the remaining eight patients, the disease status was established by follow-up demon- strating disease progression (in seven patients) and stable disease for 36 months (in one patient).
Results
Patients
Twelve patients, 10 female and two male (ages 5-71 yr), with a history of ACC underwent FDG PET imaging during the study period to assess suspected recurrent or metastatic
disease. Patient demographics, FDG PET results, and clinical findings are summarized in Table 1.
Image analysis
Ten of the 12 patients showed abnormally high FDG ac- tivity, and recurrent or metastatic ACC was subsequently demonstrated (Figs. 1 and 2). SUVs ranged from 1.9-14.2 in lesions showing abnormal FDG uptake. The tumor-to-liver activity ratio was greater than 2.0 in 10 of the 12 patients. Four of these patients had recurrent tumor in the adrenal bed, and seven had hepatic or pulmonary metastases (Table 1). All tumors were confirmed either by biopsy or follow-up CT examination. Tumor uptake was greater than liver uptake (grade 3) in each case of abnormal uptake due to ACC.
Two patients (patients 1 and 2) had abnormal findings on CT that were initially suspected to be ACC but that showed no corresponding abnormal FDG activity. Patient 1 pre- sented with a low-density lesion in the liver on CT consid- ered suspicious for recurrent disease. The SUV of 1.9 on the PET scan corresponding to this region and the tumor-to-liver activity ratio of 0.9 suggested that this was benign disease, and this was supported by a subsequent biopsy demonstrat- ing postoperative scar tissue and stable findings on subse- quent CT studies over the next 36 months. Patient 2 had both a true-positive finding (hepatic metastasis) and a true-neg- ative finding (postoperative scar tissue in the adrenal bed); both were confirmed by needle biopsy, with the patient dy- ing of progressive metastatic disease after 15 months.
Patient 5 had widely disseminated disease involving the adrenal bed, liver, and lungs. Although the bulky recurrent tumor in the adrenal bed showed substantial FDG activity (SUV 3.5), abnormal uptake was evident only in the largest of the numerous pulmonary nodules (~30%), which ranged in size from barely detectable on CT imaging to 2 cm in diameter (Fig. 3). Although there was not histological con- firmation of each of these nodules, they were classified as metastatic disease on the basis of their CT appearance and subsequent disease progression.
There was one additional false-negative finding. Patient 3 had a hepatic metastasis that showed no abnormal FDG uptake (Fig. 4). The measured SUV in the metastatic lesion was 2.9, but this was lower than the SUV of the surrounding liver and the tumor-to-liver activity ratio was only 0.7. This patient had undergone adrenalectomy at the time of initial diagnosis, 5 yr previously. The pathology report at that time described a 7-cm ACC that had invaded the adrenal capsule. At the time of follow-up 5 yr later, a 3-cm mass was evident in the inferior aspect of the right lobe of the liver on CT imaging (Fig. 4). Despite the absence of significant metabolic activity, the lesion was resected and found to be recurrent ACC.
Discussion
Our findings indicate that most ACC accumulate and re- tain FDG. However, an occasional or very small tumor may not accumulate sufficient FDG to allow detection. Other PET imaging tracers, such as [11C]metomidate, that probe char- acteristics specific to adrenal cortical lesions may prove to be more useful (14).
| No. | Age (yr) | Sex | Study | Relative FDG uptake | Size (cm) | SUV | Tumor-to-liver SUV ratio | Diagnosis | History | Confirmation |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 37 | F | PET/CT | 2 | 1 | 1.9 | 0.9 | Postoperative changes | Cushing's syndrome; right adrenalectomy 6 yr earlier; recurrence in liver 1 yr later; routine follow-up imaging | Follow-up at 36 months: stable |
| 2 | 50 | F | PET | 3 | 2.5 | 9.2 | 2.7 | Metastatic ACC | Resection of ACC 2 yr earlier; routine follow- up imaging | Follow-up: progressive disease (deceased, 15 months) |
| 3 4 | 71 51 | M F | PET/CT PET | 1 3 | 3 2.5 | 2.9 8.5 | 0.7 2.1 | Metastatic ACC Recurrent ACC | Presented 5 yr earlier with refractory hypertension, elevated aldosterone; routine follow-up imaging Hirsutism, acne, weight gain, elevated testosterone; routine follow-up imaging | Resection Resection |
| 5 | 39 | F | PET/CT | 3 | 6 | 3.5 | 2.2 | Recurrent ACC | Presented with nonfunctioning abdominal mass; routine follow-up imaging | Follow-up at 12 months: progressive disease |
| 6 | 66 | F | PET/CT | 3 | 4 | 14.2 | 4.8 | Metastatic ACC | Presented 2 yr earlier with hirsutism and elevated testosterone; routine follow-up imaging | Follow-up at 12 months: progressive disease |
| 7 | 24 | F | PET/CT | 3 | 5 | 9.5 | 4.3 | Metastatic ACC | Cushing's syndrome at presentation 1 yr earlier; routine follow- up imaging | Needle biopsy |
| 8 | 51 | F | PET/CT | 3 | 2 | 6.9 | 2.3 | Recurrent ACC | Cushing's syndrome at presentation 1 yr earlier; routine follow- up imaging | Needle biopsy |
| 9 | 8 | M | PET | 3 | 3 | 4.5 | 2.2 | Metastatic ACC | Precocious puberty at presentation, elevated plasma testosterone | Follow-up |
| 10 | 5 | F | PET/CT | 3 | 4 | 7.0 | 2.1 | Metastatic ACC | Virilization, hypertension, seizures at presentation at age 2 yr; pulmonary metastases developed, complete remission after chemotherapy; routine follow-up imaging; | Progressive disease |
| 11 | 8 | F | PET | 3 | 3 | 10.8 | 6.4 | Metastatic ACC | Precocious puberty at presentation; resection; pulmonary metastases after 6 months; complete response chemotherapy; relapse 1 yr later | Follow-up |
| 12 | 6 | F | PET | 3 | 1.5 | 3.9 | 4.3 | Recurrent ACC | Precocious puberty at presentation; resection; rising DHEAS 1 yr after resection | Follow-up |
Reference scale for relative uptake is as follows: 0 = no uptake; 1 = less than liver uptake; 2 = equal to liver uptake; 3 = greater than liver uptake. DHEAS, Dehydroepiandrosterone sulfate; F, female; M, male.
CT or MR imaging is most often used for the initial eval- uation of ACC. These anatomically based methods generally show a heterogeneous adrenal mass with variable enhance- ment of the solid components. Both techniques are useful in assessing local tumor extension, and MR imaging is partic- ularly useful for detecting vascular invasion. Considerable
efforts have been made to assess the ability of CT and MR imaging to distinguish adrenal adenoma from metastatic carcinoma. This distinction is generally based on the high lipid content of adrenal adenomas. Chemical-shift MR im- aging and low Hounsfield unit measurements on CT may demonstrate the presence of lipid, suggesting benign lesions
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(15, 16). A more recent technique distinguishes benign from malignant adrenal disease by assessing the washout char- acteristics of iv contrast agent (17, 18). FDG PET, on the other hand, relies on differences in metabolic activity to distinguish benign from malignant disease. FDG PET cannot yet distin- guish ACC from metastatic disease in the adrenal glands. Neither can it distinguish among pheochromocytoma, met- astatic disease, and lymphoma, which generally exhibit high glycolytic activity (19).
FDG PET can help to distinguish between benign and malignant adrenocortical disease. Recently, Bagheri et al. (20) showed that FDG uptake could be identified in normal ad- renal glands in 68% of patients when coregistered PET/CT images were examined. However, in the vast majority of
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normal adrenal glands that showed FDG uptake in that study, the intensity of uptake was equal to or less than that of the liver. Adrenal adenomas generally do not show ab- normal metabolic activity, and hence, in the case of an en- larged adrenal gland, PET imaging may help to distinguish adenoma from carcinoma. In the rare cases in which an adrenal adenoma does show elevated metabolic activity on
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FDG PET, the activity may reflect inflammation within the lesion (21).
In the future, FDG PET imaging will likely be used to restage disease and to evaluate patients for local recurrence and distant metastasis. The most common sites of distant metastasis of ACC are the liver, lung, lymph nodes, and peritoneum (22, 23). In our small, multi-institutional series, we found FDG PET to detect local recurrent disease reliably (within the adrenal bed), even when anatomic imaging was inconclusive, and to be somewhat less reliable for detection of metastatic disease in the liver and lungs. The sensitivity of the scan will depend on several factors, including the inher- ent metabolic activity of the individual tumor studied, re- ceiver-operator characteristics, and scanner and protocol de- tails. For patient 5, despite the largest tumor in the series, the adrenal bed lesion SUV was only 3.5, indicating that this tumor did not display as high uptake as tumors of the other patients. This may be the reason why many of the relatively large pulmonary lesions in this patient showed only faint uptake of FDG. In other patients with more metabolically active tumors, smaller lesions may be identified.
FDG PET is useful in distinguishing malignant from be-
nign adrenocortical lesions other than ACC (24-27). Most of the malignant lesions in these studies have been metastatic adrenal lesions. Two previous studies have specifically as- sessed the use of FDG PET in ACC. Becherer et al. (8) pro- spectively studied 10 patients with ACC and found FDG PET imaging to be 100% sensitive and 95% specific for malig- nancy. The authors observed that FDG-PET could detect multiple lesions that were not evident by other imaging modalities. More recently, Leboulleux et al. (9) compared the use of PET/CT to conventional thoraco-abdominopelvic CT (TAP-CT) in the diagnosis. They found that although PET/CT was more sensitive than TAP-CT, the techniques were complementary, because lesions not seen on one mo- dality were often seen on the other. One patient in their study had a liver lesion detected on TAP-CT that was not evident on PET/CT, but it is not clear whether this was a false- negative PET/CT finding or whether it was because the liver lesion was benign (e.g. a hemangioma or cyst) or too small to reasonably be expected to be detected on CT. The patient with a 3-cm liver lesion that was proven metastatic ACC is the only false-negative ACC that we have been able to document.
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Conclusion
FDG PET is useful for the detection of recurrent and met- astatic ACC. However, an occasional tumor and small pul-
monary lesions may not accumulate sufficient FDG to allow detection, resulting in false-negative findings. Additional evaluation is required to determine the utility of FDG PET for monitoring the response to chemotherapy and/or radiotherapy.
Acknowledgments
We thank Sandra Gaither for secretarial expertise and Sharon Naron for editorial assistance in the preparation of this manuscript.
Received December 2, 2005. Accepted April 6, 2006.
Address all correspondence and requests for reprints to: Barry L. Shulkin, M.D., Department of Radiological Sciences, St. Jude Children’s Research Hospital, 332 North Lauderdale, Mail Stop 752, Memphis, Tennessee 38105-2794. E-mail: Barry.shulkin@stjude.org.
This work was supported by U.S. Public Health Service Grants CA 54216 (to B.L.S.) and MO1-RR00042 (General Clinical Research Center of the University of Michigan), Cancer Center Support Grant CA 21765, Pediatric Oncology Education Program Grant 5R25 CA23944, and by the American Lebanese Syrian Associated Charities (ALSAC).
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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.