| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Surgery (J.H., P.H.), Radiology (A.S.), and Medical Sciences (O.L.), Uppsala University Hospital and Uppsala Imanet AB (O.L., B.L., M.B.), Uppsala, Sweden
Address all correspondence and requests for reprints to: Dr. Per Hellman, Department of Surgery, University Hospital, SE-751 85 Uppsala, Sweden. E-mail: per.hellman{at}surgsci.uu.se.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Objective: We evaluated 212 MTO-PET examinations in 173 patients to identify its role in the management of adrenal tumors.
Design: Seventy-five histopathological examinations from 73 patients were retrospectively analyzed.
Setting: All examinations were performed at a referral center.
Patients: Patients who were operated or biopsied due to adrenal tumors had histopathological diagnoses of adrenocortical adenoma (n = 26), adrenocortical cancer (ACC; n = 13), adrenocortical hyperplasia (n = 8), pheochromocytoma (n = 6), metastasis (n = 3), and tumors of nonadrenal origin (n = 19).
Main Outcome Measures: The main outcome measures were statistical analyses and findings while scrutinizing images. The hypothesis that MTO-PET is of value in the management of adrenal tumors, especially incidentaloma, was stated before data collection.
Results: Sensitivity was 0.89 and specificity was 0.96 for MTO-PET in proving adrenocortical origin of the lesions. Pheochromocytomas, metastases to the adrenal gland, and nonadrenal masses were all MTO negative. PET measurements using standardized uptake values (SUV) in pathological adrenocortical tissue could differentiate lesions larger than 1–1.5 cm from normal adrenocortical tissue. SUV was higher in aldosterone-hypersecreting adenomas, and the SUV ratio between the tumor and the contralateral gland was significantly higher in all hormonally hypersecreting adenomas as well as in ACC.
Conclusion: MTO-PET is a specific and sensitive method for diagnosing adrenocortical tumors. MTO-PET is useful in the imaging work-up of adrenal incidentalomas and may be beneficial for the examination of patients with primary aldosteronism or ACC.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
. In addition, of the 75 MTO-PET examinations, 55 were performed using an algorithm allowing more thorough analyses of MTO uptake and signaling (see Table 1).
|
PET
Carbon-11 was produced on a Scanditronix MC-17 cyclotron (Scanditronix-Wellhöfer, Uppsala, Sweden). The synthesis of [O-methyl-11C]MTO was performed as previously described (6, 7). All 75 patients were examined in either a GE 4096 whole-body PET scanner (GE Medical Systems, Milwaukee, WI) or a Siemens ECAT HR+ (Siemens, Munich, Germany) after at least 4 h of fasting, allowing free intake of clear liquids. The GE PET camera simultaneously produced 15 contiguous 6.5-mm axial slices with an in-plane resolution of 5–6 mm, and the Siemens ECAT PET camera produced 63 contiguous 2.5-mm axial slices with an in-plane resolution of 5 mm. A recent CT examination was used as a means of positioning the tumor region in the field of view of the PET camera and for anatomical correlation of the PET images. Patients were placed supine, and a laser beam was used to position the tumor region within the field of view of the PET scanner. A 10-min transmission scan was generated with an external rotating germanium-68 pin to correct the ensuing emission scan for attenuation. After a rapid iv bolus of approximately 10 MBq/kg (mean ± SD, 700 ± 200 MBq) [11C]MTO, a 45-min dynamic examination sequence was started.
Image reconstruction and data analysis
From MTO-PET in 55 patients, dynamic images were reconstructed in a 128 x 128 matrix with a pixel size of 4 x 4 mm using a 6-mm Hanning filter and correction for attenuation and scattered radiation. The radioactivity concentrations in these images were recalculated to provide images of standardized uptake values (SUV), whereby the radioactivity concentration (becquerels per cubic centimeters) was divided by the injected dose per gram of body weight. Given a tissue density of 1.0 g/cc, this calculation provides an estimate of the tissue tracer accumulation relative to a presumed even radioactivity distribution in the body as a whole, which corresponds to an SUV of 1.0.
PET measurements
The radiologist investigating the images (A.S.) was blinded for the radiological data from the CT scans, but had clinical information regarding the patients, such as known ACC or whether the PET study was performed due to an incidentaloma. Regions of interest (ROIs) were drawn manually in the summation images in normal adrenal, including contralateral glands as well as adrenal tumors. In each tissue a region was drawn in the area with the highest radioactivity concentration, designated the hot spot (ROIhs), comprising four contiguous pixels (0.64–1.0 cm2). In the liver a large circular ROI was drawn. SUV in the ROIs or SUVhs in the ROIhs were calculated 15–45 min after injection (Table 1
). To exclude possible hormonal influence on these PET measurements, only the contralateral adrenal gland in patients with tumors of nonadrenal origin was considered normal. MTO uptake in a normal gland is characterized by a homogenous signal without any hot spots. In the remaining patients, the nontumorous adrenal gland was designated contralateral.
A true positive MTO-PET result was defined as a MTO-positive tumor corresponding to an adrenocortical tumor at histopathological examination (Fig. 1). A cortical tumor had a heterogeneous metomidate uptake with an hs, correlating to the tumor seen on CT, as judged by qualitative criteria. A false-negative MTO-PET result was noted when the examination failed to detect a cortical tumor diagnosed on CT and verified at surgery and/or histopathological examination. Nonadrenocortical lesions at MTO-PET that were verified as such by histopathological examination, but were diagnosed as tumor lesions on CT, were considered true negative observations (Fig. 1D). These lesions were totally devoid of metomidate uptake.
|
One-way ANOVA with Dunnett’s posttest was performed using PRISM version 4.01 for Windows (GraphPad, Inc., San Diego, CA). Values are presented as the mean ± SD.
Ethical considerations
The study comprises retrospective data partly included in other studies (6, 7, 9) that used informed consent and approval of the local ethics committee. Some recent MTO-PET investigations were performed in newer, not yet published, studies, also using informed consent and with approval from the local ethics committee. The hospital has also decided that PET using MTO is a routine clinical method for patients with suspected or known ACC. Therefore, some recent patients have undergone MTO-PET without ethical approval due to the clinical routine status.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Forty-two MTO-PET examinations revealed MTO-positive tumors. The size of these lesions at the corresponding CT examination averaged 5.5 cm (range, 1–20 cm). The sensitivity of MTO-PET for proving the adrenocortical origin of a lesion was 0.89 (42 of 47 histopathologically proven adrenocortical tumors). Thus, five MTO-PET examinations proved false negative. In two of these cases, the surgical finding and histopathological diagnosis demonstrated an almost completely necrotic ACC (Fig. 1). In one of these tumors, a narrow, faintly visible brim that accumulated MTO surrounded the necrosis, whereas the other tumor was completely devoid of MTO uptake. In these two patients, no MTO-positive extraadrenal metastases helped to reveal the adrenocortical origin of the tumor. Both patients were operated on because the size of the tumors exceeded 4 cm, this being an absolute indication for surgery in our department.
The other three of the five false-negative MTO-PET examinations were related to tumor size. In two of these patients, small Conn adenomas were found at surgery (
1 cm), and the third patient had a discrete area of nodular hyperplasia (1 cm). Overall, the lower size resolution limit when an SUV in an enlarged adrenal differs from the contralateral normal adrenal was approximately 1 cm. In our material, the smallest tumors were in patients with PA, which was a reason for their examination.
One false-positive result occurred in one patient, rendering a specificity of 0.96. This patient had a 20-cm lesion adjacent to the left kidney. The tumor itself was MTO negative, but a small uptake was noted in the right lower part of the abdomen near the parietal peritoneum, and a metastasis from an ACC was suspected. The adrenal tumor proved to be a leiomyosarcoma, and no pathological lymph node was found after exploration and sampling at surgery. Thus, the false-positive uptake in the lower abdomen misled the interpretation of the negative large mass, which, nevertheless, was operated upon due to its size. This patient was denoted false positive due to the misinterpretation of the PET images, although the tumor itself was negative.
Pheochromocytomas, metastases to the adrenal gland, and benign nonadrenocortical lesions were all MTO negative (Fig. 1).
PET measurements
The results of PET measurements are described in Table 1. Almost completely necrotic ACC, devoid of MTO uptake, were excluded from the statistical analyses of the SUV measurements. SUVhs did not discriminate between malignant necrotic tumors and tumors with a benign cause of necrosis, e.g. fibrosis secondary to bleeding.
The mean SUVhs in Conn adenomas was significantly higher than that in normal adrenal glands (P < 0.01). There were no significant differences in SUVhs between the contralateral glands regardless of type of pathology or hormonal activity in the affected gland. However, when the quotient between the tumor and the contralateral adrenal gland was considered, this was higher for Conn adenomas, Cushing adenomas, and ACC than that of normal adrenal glands (left/right; P < 0.01, P < 0.05, and P < 0.01, respectively). The SUV in the liver was similar in all groups.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Several incidentalomas may be characterized at CT as benign cortical adenomas based on their low attenuation values at native (not enhanced with contrast) examination, indicative of a lipid-containing tumor. Administration of iv contrast leading to enhancement of the attenuation signal also supports a cortical solid lesion. Recently, it has been shown that attenuation measurements at CT performed 10 min after contrast medium injection adds information to this characterization, because the contrast medium washout is faster in adenomas than in ACC, pheochromocytomas, and metastases (12). This technique may decrease the number of uncharacterized incidentalomas.
However, in a large proportion of patients, the incidentalomas still escape characterization by CT, and additional radiological examination by magnetic resonance imaging (MRI) is required. Using MRI signal sequences in and out of phase, a loss of signal is detected in the latter phase in a fat-containing lesion (chemical shift). Thus, even after radiological workup, including additional CT and/or MRI, up to one third of incidentalomas remain uncharacterized (9).
The large clinical problem of identifying incidentalomas that require treatment from benign hormonally silent lesions demands sensitive and reliable methods. Apparently, characterization by CT and MRI is not fully sufficient. The lack of sensitivity of CT and MRI in this respect has resulted in protocols including repetitive follow-up CT examinations during up to 18 months of surveillance to detect growing lesions that are suspect for cancer and thorough biochemical analyses for diagnosis of hormonal hypersecretion. The increased detection of PA adds to this quantitative problem, because associated adrenal tumors in such patients need to be characterized.
We have previously demonstrated that MTO is a promising and sensitive PET tracer for the imaging of adrenocortical tumors (6, 7, 9, 11). This finding has been supported by other groups, although these studies have included only a small numbers of patients (10, 11). Because of the binding of MTO to the 11ß-hydroxylase activity in the adrenal cortex, MTO-PET may divide incidentalomas into two major groups with a high specificity. MTO-positive lesions constitute the adrenocortical tumors, i.e. adrenocortical adenomas or hyperplasias and ACC, whereas the MTO-negative lesions constitute all other tumors. The present retrospective correlative study in a larger number of patients comprised a subset of 75 (of 212) patients who underwent MTO-PET, but who also underwent surgery or needle biopsy for subsequent histopathological diagnosis.
The physical resolution of the PET scanner is approximately 0.5–1.0 cm. Smaller tumors may be depicted given that the tracer accumulation is high. In our material, the smallest lesion depicted at MTO-PET measured approximately 1 cm. Therefore, discrimination between uni- or bilateral adrenal disease in cases of PA may be difficult based on size criteria only.
According to data presented in Table 1, the SUVhs may discriminate Conn adenomas from normal and contralateral adrenal glands. In contrast, the quotient between the tumor and the contralateral adrenal gland discriminated between aldosterone- as well as cortisol-hypersecreting adenomas and ACC from normal adrenal glands. The SUVhs in the contralateral adrenal in patients with hormonal hypersecretion was similar to that in patients with nonfunctioning tumors and in patients with tumors not emanating from the adrenal gland. An assumed suppression of [11C]MTO accumulation in the contralateral adrenal by hormonal hypersecretion thus could not be verified.
One may speculate that the MTO uptake correlates to the amount of expressed CYP11B enzymes, relating to the increased number of cells. In addition, the SUVhs may correlate to cellular density. These assumptions would indicate a lack of relation between hormonal activity and MTO uptake or SUVhs. In contrast, an increased enzyme expression per cell, possibly resulting in higher SUVhs, may be associated with increased hormonal secretion. This hypothesis may be supported by our finding of higher SUVhs values in aldosterone-hypersecreting adrenal glands. However, additional cellular analyses are mandatory to clarify these questions.
Indeed, in certain situations, MTO-PET may be difficult to interpret. As also previously noted in patients suffering from ACC, the lack of MTO uptake may be due to large necroses. The lack of signal could not be differentiated from necroses emanating from other causes, e.g. fibrosis secondary to bleeding. Furthermore, differentiation between a central noncortical tumor, replacing the adrenal gland, and an ACC with extended necrosis is difficult. A false-negative result is probably difficult to avoid when facing the latter, unless MTO accumulation in coexisting metastases leads to the diagnosis. In clinical practice, most ACC exceeds the generally accepted size of 3–4 cm, which indicates surgery, and/or demonstrate hormonal adrenocortical hypersecretion. However, the absence or presence of metastases at MTO-PET in these cases adds information necessary for the therapeutic decision, timing of surgery vs. chemotherapy, etc. (8, 9).
The statistical analyses in the present study allow the possibility of performing prospective suggestions of the origin of the adrenal enlargement. In an individual patient, a tumor SUVhs higher than 24.3 would be equal to a 95% risk of a cortical adenoma or an ACC. If the SUVhs is more than 32, there is a 95% risk of a Conn adenoma. A more robust figure may, instead, be the quotient between the SUVhs in a tumor and that of the contralateral adrenal gland. With a quotient more than 1.4, there is a 99.5% risk of adrenocortical tumor.
As discussed above, a considerable proportion of patients are subjected to repetitive CT and/or MRI examinations to exclude lesion growth, but the nature of the incidentaloma remains uncharacterized. However, different investigational algorithms are used in different parts of the world, where the National Institutes of Health consensus propose fewer CT scans than many European programs (13). By contrast, MTO-PET performed as the first imaging procedure in patients with incidentalomas, replacing repetitive CT and MRI, would divide the patients into two groups. One larger group would comprise patients with adrenocortical tumors in whom the future workup may be limited and concentrated on possible adrenocortical hormonal hypersecretion and follow-up according to size criteria. In contrast, a second smaller group, with varying tumor diagnoses, would require more extensive workup. With recently developed PET-CT scanners, combining both modalities in the same gantry, this characterization will be even more refined, because the uptake of MTO or its absence may be demonstrated at the same time as attenuation measurement of the tumor is performed. In addition, with the development of more stable MTO tracers, such as those labeled with 18F, the technique will become more widely available.
In conclusion, MTO-PET facilitates the diagnosis of adrenal tumors (6, 8, 9, 10, 11) and contributes to the staging of ACC, follow-up after surgical and oncological treatment, and restaging in recurrent disease (8, 9). The present results point toward an as yet not fully proven clinical role for MTO-PET in the evaluation of the increasing number of incidentalomas and PA found. Ideally, MTO-PET may in some cases also replace the invasive, and often technically difficult, adrenal venous sampling procedure, although tracers correlating to enzymatic and secretory activity, rather than mere expression, possibly enhance functional resolution. To make MTO-PET more available, an MTO analog labeled with a more long-lived positron emitter than 11C has been developed.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
J.H., A.S., and P.H. have nothing to declare. Ö.L. and B.L. are employed by Uppsala Imanet AB, and M.B. was previously employed by Uppsala Imanet AB.
First Published Online January 10, 2006
Abbreviations: ACC, Adrenocortical cancer; CT, computed tomography; hs, hot spot; MRI, magnetic resonance imaging; MTO, metomidate; PA, primary aldosteronism; PET, positron emission tomography; ROI, regions of interest; SUV, standardized uptake value.
Received October 14, 2005.
Accepted January 4, 2006.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  S. Hahner, A. Stuermer, M. Kreissl, C. Reiners, M. Fassnacht, H. Haenscheid, F. Beuschlein, M. Zink, K. Lang, B. Allolio, et al. [123I]Iodometomidate for Molecular Imaging of Adrenocortical Cytochrome P450 Family 11B Enzymes J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2358 - 2365. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Libe, A. Fratticci, and J. Bertherat Adrenocortical cancer: pathophysiology and clinical management Endocr. Relat. Cancer, March 1, 2007; 14(1): 13 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. F. Young Jr. The Incidentally Discovered Adrenal Mass N. Engl. J. Med., February 8, 2007; 356(6): 601 - 610. [Full Text] [PDF]
|
|
Read all eLetters
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
