FDG-PET in Adrenocortical Carcinoma
Alexander Becherer1 MD, Heinrich Vierhapper2 MD, Christian Pötzi1 MD, Georgios Karanikas1 MD, Amir Kurtaran1 MD, Jörn Schmaljohann1 PhD, Anton Staudenherz1 MD, Robert Dudczak1,3 MD, and Kurt Kletter1 MD PhD
1Department of Nuclear Medicine; 2Department of Endocrinology and Metabolism, University of Vienna; 3Ludwig Boltzmann Institute for Nuclear Medicine University of Vienna, Vienna, Austria
Adrenal cortical carcinoma (ACC) is a rare malignant neoplasm with a poor prognosis. Radical surgery of the primary tumor and of local as well as of distant recurrence is the only effective treatment, and re- quires accurate and early localization of recurrent tumors. In this regard, we prospectively scanned 10 patients with ACC, 8 during follow-up and 2 at primary work-up. In all patients PET scans from the neck to the upper thighs were obtained 45 minutes after injection of 370 MBq [18F]FDG. Reading was done visually, with the investigator blinded to the results of other diagnostic modalities. All known sites of ACC lesions showed markedly increased FDG uptake. In 3 patients, previously unknown lesions were identi- fied by PET in the lung (one lesion), the abdomen (3 lesions), and the skeleton (multiple), respectively. One false positive liver focus was shown by PET aside from the true positive lung metastases in the same patient. The sensitivity/specificity of PET based on different organs was 100/97%, that based on the num- ber of PET-detected lesions (N = 23) was 100/95%. PET altered or influenced the tumor stage in 3/10 patients, modifying the subsequent therapeutic management in 2/10 patients. We conclude that FDG-PET is highly useful in ACC and should be included in the work-up for initial staging as well as for follow- up.
Key words: Adrenocortical carcinoma, positron emission tomography, fluorodeoxyglucose
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare neo- plasm with a poor prognosis. Its annual incidence ranges from 0.6 to 1.67 per million population,1 accounting for 0.02% of all cancers.2 Tumor dis- semination is present in 50 percent at initial di- agnosis and occurs in about 80 percent of pa- tients, most commonly to the lung, liver, and adjacent organs.3,4 The incidence of hormone- producing tumors varies from 40 to 80 percent.5,6 ACC might present with endocrinological symp-
toms related to the predominant steroid hormone, most frequently Cushing’s syndrome with or without virilization; this condition usually causes ACC to be diagnosed. In these cases urine and serum hormone levels might serve as tumor markers for post-surgical follow-up, in addition to radiological modalities. However, approxi- mately one half of the patients mainly produce inactive hormone precursors, because of which the diagnosis is delayed. The same is true for tu- mors with no secretory activity.6 Thus in a con- siderable number of cases, diagnosis and follow- up are mainly based on tumor imaging. The high likelihood of the presence of distant metastasis necessitates extensive radiological investiga- tions, including intravenous pyelography, sonog- raphy, computed tomography (CT), magnetic res- onance imaging (MRI), and angiography.”
Positron emission tomography (PET) with 2- [18F]-fluoro-2-deoxy-D-glucose (FDG) was shown to be effective in the detection of a wide range of malignant tumors.8-10 The usefulness of PET in patients with various cancers for the eval- uation of adrenal incidentalomas concerning met- astatic etiology has been proven.11 A recent re- port also included primary adrenal lesions in patients with no other malignancies and showed that PET permits non-invasive differentiation of malignant adrenal lesions from benign neoplas- tic ones in these patients as well.12 However, probably due to the rareness of the disease, the value of PET particularly addressing ACC has not been determined. Using PET, we prospec- tively studied patients with histologically proven adrenal carcinomas.
PATIENTS AND METHODS
Patients
Included in the study were 10 patients (3 females and 7 males) with a mean age of 48 years (range, 38-74 years). The patients had been consecu- tively referred for a PET scan as an additional di- agnostic aid parallel to conventional follow-up procedures consisting of laboratory investiga- tions, ultrasound and CT. Two patients were stud- ied at the initial diagnosis of ACC, one before, and one after surgery. The remaining 8 patients had a mean disease duration of 74 months (range, 24-197 months) before PET. All of them had un- dergone surgery for the primary tumor and were under treatment with 1,1-dichloro-2-(o-chloro- phenyl)-2-(p-chloro-phenyl)ethane (o,p’ DDD, mitotane) during the time of the PET study.13 Three patients with metastatic disease also re- ceived suramin periodically, but had paused this therapy at least 3 months before the FDG-PET.
None of the 2 patients studied at primary work- up had an endocrine active tumor. In the follow- up group 3 patients had endocrinologically active tumors, 2 with a history of Cushing’s syndrome and one with feminization.
Nuclear Medicine Procedure
FDG was synthesized by nucleophilic reaction using an automated module (GE Microlab, Gen- eral Electric Medical Systems, Milwaukee, WI). After an at least 5 hours fast, approximately 370 MBq of FDG were injected intravenously. At tracer injection, blood glucose levels were below
6 mmol/l (110 mg/100 ml) in all patients. After an uptake period of 45 minutes the patients were scanned from the neck to the proximal thigh with- out attenuation correction in a full-ring PET scan- ner (GE Advance, General Electric Medical Sys- tems, Milwaukee, WI) in the 2-D mode. For regions with focally increased FDG uptake, ad- ditional attenuation corrected scans were ob- tained using the built-in 68Ge rod sources. Scans were reconstructed by filtered back projection with a Hanning filter, at a cutoff value of 12 mm. Optionally, in some patients an iterative recon- struction with a segmented attenuation correction algorithm was performed.
The PET scans were read visually without knowledge of the results of other tests. Every hot spot not explainable by physiologic glucose me- tabolism or urine activity was considered as pathologic. Over areas with focally increased up- take, regions of interest (ROIs) were drawn and the standardized uptake values (SUVs) of the le- sions calculated from the attenuation corrected slices for documentation purposes only but not for characterization of the lesions. PET findings were compared with computed tomography (CT) and/or ultrasound (US). In two cases, after the PET scan the patients underwent surgery and a histological diagnosis was available.
RESULTS
In all subjects, the diagnosis of ACC was estab- lished on the basis of histological criteria. All pri- mary tumors had shown aggressive invasive growth and intravascular spread. The actual clin- ical stage of the disease was based on conven- tional imaging and hormone levels, verification was obtained by follow-up over at least 7 months if no histological diagnosis was available.
In the follow-up group, 5 patients were supposed to be free of tumor at the time of PET based on conventional imaging and laboratory parameters; 2 patients had known pulmonary metastases; and in one patient who had undergone lung resection due to pulmonary metastases 8 months prior to PET, a recent CT showed a single pulmonary node indicative of local recurrence (Fig. 1a). The high FDG uptake suggested malignancy of this nodule as well as of a second FDG-avid nodule which was shown on CT 4 months later (Fig. 1b). Both le- sions were confirmed as recurrent pulmonary ACC metastases by surgery. In the same patient, an ad- ditional small focus in the left renal fossa proved
A
C
B
to be tumor recurrence on the autopsy performed 9 months after PET (Fig. 1c). In the 2 patients with known lung metastases the lesions were shown ac- curately by PET. PET detected a hypermetabolic pararenal soft tissue mass in one of the 5 patients considered to be in remission (Fig. 2). Subsequent surgery confirmed a local recurrence of ACC likely caused by cell implantation during surgery of the primary tumor.
Of those studied at initial diagnosis, in one pa- tient the primary tumor was in situ with markedly FDG-uptake. In a second patient who had under- gone surgery of the primary 2 weeks before PET, multiple small pulmonary metastatic lesions mea- suring up to 10 mm in size were known to exist before FDG-PET. In addition to pathological tracer uptake throughout the lungs and visualiza- tion of foci measuring 8 to 10 mm, PET detected
multiple osseous foci, which were confirmed to be malignant lesions by X-ray and CT (Fig. 3).
Overall, PET showed 23 lesions with a correct positive result in 22 lesions in 6 patients. Seven lesions were found in 5 of the 6 patients, multi- ple lung and bone metastases were present in the last one. For calculation of sensitivity and speci- ficity based on the number of lesions, in the lat- ter patient only 10 of the multiple tumor mani- festations were taken into account. PET showed all verified lesions in the 6 patients while CT missed two subsequently confirmed foci in pa- tient no. 3 (Table 1). In one patient with true pos- itive lung lesions, PET revealed an intrahepatic focus which was not confirmed during the fol- low-up period of 6 months. Therefore this was classified as a false positive PET-finding. The le- sion based sensitivity/specificity for PET was
100%/95%, that of CT 89%/100%; when cate- gorizing the lesions into different regions resp. organ systems (lungs, bone, liver/abdominal retroperitoneal), sensitivity/specificity of PET was 100%/97%, that of CT 88%/100% (Table 1).
PET was able to alter or widen the M stage in 3 patients: In one patient from M0 to M1, in an- other from Mx to M1, and, finally, in one M1 pa- tient in addition to the known pulmonary metas- tasis, multiple subsequent radiologically verified bone metastases were shown. One patient in the initial diagnosis group had a normal PET aside from the primary tumor, causing her to be shifted from Mx to M0, which was in concordance with all other staging procedures.
The lesions had an SUV of 7.4 + 3.4 (mean ± S.D.) with the lowest value of 3.8 in the false pos- itive liver focus.
DISCUSSION
In contrast to previous investigations dealing with the value of PET in the evaluation of adrenal masses, mostly of secondary types,11,12 our study is the first that exclusively focused on patients with ACC.
Unlike other endocrinologically active tumors, mainly derived from the enterochromaffine cells, ACC is a malignancy with a poor prognosis. The median survival in a recent evaluation was 17 months,14 the overall 5-year survival is less than 35 percent, with an increase to 45 percent in cases of complete resection.15 Although the majority of tumors are functioning at initial diagnosis, recur- rent tumors may lose their endocrinological ac- tivity. Therefore, follow-up needs to focus on imaging modalities.
The high likelihood of the presence of a re- current disease is underlined by our detection of previously unknown metastases in 2 of 8 patients during follow-up. In the 2 patients studied at pri- mary diagnosis, bone involvement in addition to the known lung metastases was found in one. Al- though malignant adrenal masses of different ori- gin have been accurately characterized by MR in a recent study,16 FDG-PET might offer advan- tages over MR in terms of demonstrating locore- gional tumors as well as metastatic disease in one single scan. Furthermore, metabolic changes in incipient malignant lesions as demonstrated by FDG are known to precede anatomical changes
by up to several months.17 This suggests PET as an important imaging modality in ACC for fur- ther therapeutic management as it is a fact that an aggressive surgical approach to recurrent and metastatic disease should be adopted whenever possible.18-20
In this regard, therapeutic management was in- fluenced in 2 patients who underwent surgical re- section of the metastases after PET. In one pa- tient this was the case immediately after PET had detected the local recurrence and in the other with a latency of 5 months, when CT also became pos- itive due to the now greater tumor expansion al- ready detected by PET previously.
In cases of incomplete resection or in already metastasizing ACC, chemotherapeutic treatment with the specific adrenocorticotropic drug mi- totane13 and different regimens containing cis- platin21,22 provide better disease control. Suramin, an antiparasitic drug, has also been shown to be effective against ACC in vitro and in vivo in selected patients, in whom it may be of marked therapeutic benefit.23,24 Thus, for sur- gical and chemotherapeutical options, accurate knowledge of the presence and location of metas-
| Disease duration (months)/ Hormonal 1 activity | Primary tumor | Mitotane | PET-positive lesions by regions | Remarks | |
|---|---|---|---|---|---|
| Primary group | |||||
| pt. 1 | 0/none | in situ | no | adrenal (one lesion, known) | no metastases present |
| pt. 2 | 0/none | resected | no | lung (multiple, known), bone (multiple, unknown) | PET after surgery of the primary tumor |
| Follow-up group | |||||
| pt. 3 | 76/none | resected | yes | lung (2 lesions, one unknown) iliacal (one lesion, unknown) | history of liver metastases; autoptic verification |
| pt. 4 | 40/cortisol | resected | yes | lung (3 lesions, known) | history of local relapse |
| pt. 5 | 64/none | resected | yes | none | true negative PET |
| pt. 6 | 24/none | resected | yes | lung (4 lesions, known) liver (one lesion, false positive) | |
| pt. 7 | 40/none | resected | yes | retroperitonal (one lesion, unknown) | local relapse, surgical verification |
| pt. 8 | 24/cortisol | resected | yes | none | true negative PET |
| pt. 9 | 199/estrogen | resected | yes | none | true negative PET; history of lung metastases |
| pt. 10 | 76/none | resected | yes | none | true negative PET |
tases is crucial. FDG-PET provides additional di- agnostic information and might therefore con- tribute to early and adequate treatment of ACC. Mitotane does not seem to influence the FDG- uptake of the tumors in a negative manner as all patients in the follow-up group received the drug and no false negative PET scan was observed. The possible effects of suramin on FDG-uptake of ACC lesions, however, remain to be deter- mined because no patient received it when hav- ing the PET study.
Our results which were blinded to all other imaging modalities show that the visual reading approach is accurate when calculating sensitiv- ity/specificity based on the number of lesions as well as based on organ systems with a PET sen- sitivity of 100% and a specificity of 95% and 97%, respectively. The patient number is too small to determine a cutoff for the SUV, how- ever, the lowest SUV of all lesions was observed in the only false positive spot.
In conclusion, we found FDG-PET to be a highly helpful imaging method in ACC for the detection of primary and metastatic disease. In particular, the chance of surgical resection of re- current disease, which is the only therapeutic op- tion that improves prognosis, might be offered earlier if the patients are monitored regularly with FDG-PET. We therefore suggest FDG-PET as an important imaging procedure for staging and fol- low-up in patients with ACC, especially when there is high clinical suspicion for recurrence or metastases in spite of negative anatomical results and in those with endocrinologically inactive tu- mors. PET can be used as whole-body scan, tar- geting other imaging modalities for confirmation and better anatomical identification.
ACKNOWLEDGMENTS
The authors acknowledge the technical assistance of R. Bartosch, I. Leitinger, G. Wagner, and B. Wurzer in acquiring the PET scans, and the con- tribution of E. Bartosch, H. Eidherr, A. Krcal, and M. Mitterhauser in FDG production and quality control.
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