ENDOCRINE PRACTICE Rapid Electronic Article in Press
Original Article
EP-20158-0616
LARGE ADRENAL INCIDENTALOMAS REQUIRE A DEDICATED DIAGNOSTIC PROCEDURE
Vincent Amodru MD 1, David Taieb MD, PhD 2,3, Carole Guerin MD4, Nunzia Cinzia Paladino MD 4, Thierry Brue MD, PhD 1, Frederic Sebag MD 4, Frederic Castinetti MD, PhD1
From : Aix Marseille Université, Assistance Publique Hôpitaux de Marseille, Marseille, France 1Marseille Medical genetics, CRMR HYPO, Department of Endocrinology, La Conception Hospital; 2Department of Nuclear Medicine, La Timone University Hospital, Aix-Marseille University, Marseille, France; 3European Center for Research in Medical Imaging, Aix- Marseille University, Marseille, France; 4Department of Endocrine Surgery, La Conception hospital.
Running title : Outcome of adrenal tumors larger than 4 cm
Corresponding author : Frederic Castinetti, MD, PhD Department of Endocrinology, 147 boulevard Baille, La Conception Hospital, 13005 Marseille, France. Email : frederic.castinetti@ap-hm.fr
ABSTRACT
Introduction: The management of large non secreting adrenal tumors (at least 4 cm) is still a matter of debate as it is unclear whether imaging, especially 18F-FDG, can be used to characterize their potential malignancy. Moreover, the risk of new hypersecretion in non- operated tumors is uncertain. Our aim was to better characterize these large adrenal incidentalomas.
Methods: Patients followed in our Center for a non-secreting large (at least 4 cm) adrenal incidentaloma, with an initial CT and 18F-FDG PET CT, were retrospectively included. Patients who were not operated after initial diagnosis had to be followed with clinical, biological and imaging evaluations for at least 3 years or till delayed surgery.
Results: 81 patients were included in the study: 44 patients (54.3%) had initial surgery while 37 were followed, including 21 (25.9%) who were operated after a mean of 19 months. Among the 65 operated patients, 13 (20%) had a malignant lesion (3 with metastasis, and 10 with adrenocortical carcinoma): unenhanced CT < 10 showed 85.6% sensitivity and 78.8% specificity; all had a 18F-FDG uptake ratio > 1.5. Among the 24 patients who were followed for at least 3 years, 5 (20.8%) finally presented hypercortisolism (4 subclinical).
Conclusions: As expected, large adrenal tumors are at higher risk of malignancy. The combination of unenhanced CT < 10 and 18 F-FDG PET ratio < 1.5 prove to be reassuring and might lead to a close follow-up rather than immediate surgery. Hormonal follow-up should be focused on the risk of hypercortisolism.
Abbreviations:
ACC = Adreno Cortical Carcinoma; CT = Computed Tomography; ESE = European Society of Endocrinology; ENSAT = European Network for the Study of Adrenal Tumors; FDG PET CT = Fluoro- D glucose Positron Emission Tomography; HU = Hounsfield Units; ODST = Overnight Dexamethasone Suppression test; LDDST = Low Dose Dexamethasone Suppression test; UFC = Urinary free Cortisol; ULN = Upper Limit Normal; ROC = Receiver Operating Characteristics; SUV = Standard Uptake Value.
INTRODUCTION
The European Society of Endocrinology and the European Network for the Study of adrenal tumors (ESE/ENSAT) have recently proposed an algorithm regarding the management of adrenal incidentaloma, ie. an asymptomatic adrenal mass detected on imaging performed for a clinical complaint not due to an adrenal disease (1). For non-secreting adrenal incidentalomas of less than 4 cm, these guidelines emphasized the need for a dedicated imaging to ascertain the benign nature of the lesion. Doubtful cases should lead to immediate alternate imaging, a 6-12 months imaging follow-up or surgery as decided by a multidisciplinary expert team. Hormonal work-up should be repeated if clinical signs or comorbidities appear during the follow-up of patients (1). Since then, another study emphasized the role of 18F-FDG PET/CT for characterization of adrenal lesions with undetermined nature on washout adrenal CT (2).
In contrast, there is still some uncertainty regarding the optimal approach of patients with larger adrenal masses (equal or higher than 4 cm) (3). This cut-off was based on several studies summarized in the review by Barzon et al., showing that the proportion of malignant lesions
was very low for tumors < 4 cm, and could reach up to 50% in tumors > 6 cm (4,5). More in detail, Aso et al., reported the pathology of 210 adrenal tumors of a mean size of 4.9 cm, without any follow-up data of non-operated patients; that was the same issue for Bastounis et al. (6,7). Tutuncu included hypersecreting tumors, ie. tumors for which surgery would have been advised whatever the size (8). Of note, none of these studies used modern imaging techniques to define whether the surgery was or not necessary. This is why the ESE/ENSAT guidelines acknowledged that “the literature on follow-up of non-operated large adrenal incidentalomas is scarce”. Since these guidelines, 2 studies were published on adrenal incidentalomas. Hong et al. reported 449 patients followed at least 6 months for non- functional adrenal lesions: however, only 16 of these lesions were measuring 3 cm or more. From the patients initially treated by adrenalectomy, 19 malignant incidentalomas with a size above 4 cm had an attenuation above 10 HU (9). More recently, the Mayo Clinic team described its large experience with 705 adrenal tumors larger than 4 cm at diagnosis, reporting a high rate of malignancy of 31% in these patients. Among the 215 malignant tumors, all had an attenuation above 10 HU. Of note, a large part of these tumors were not diagnosed incidentally: though the authors improved the knowledge of large incidentaloma characteristics by reporting the efficacy of unenhanced CT in diagnosing malignancy, they did not give data about 18F-FDG PET/CT nor appearance of hypersecretion during follow-up (10). The aim of our study was to evaluate the nature and the outcome of non-secreting adrenal tumors equal to or larger than 4 cm, followed in our department: we were specifically focusing on the accuracy of classical imaging indices associated with benignity (unenhanced CT ≤10 HU, wash-out > 45%, adrenal mass SUVmax: liver SUVmax uptake ratio (18F-FDG uptake ratio) on 18F-FDG PET/CT < 1.5), and appearance of hypersecretion during follow-up, in the aim of
defining whether the criteria used for adrenal masses < 4 cm could be applied to masses > 4 cm.
MATERIAL AND METHODS
Study design and subjects
We retrospectively analyzed the data of 1981 patients referred to our department for an “adrenal disease” between 2007 and 2015. Only those who fulfilled the following criteria were included: (1) initial diagnosis of adrenal incidentaloma with a largest size at least equal to 4 cm, (2) normal secretory status at diagnosis, defined by normal urine and plasma metanephrins and normetanephrins, normal renin/aldosterone ratio, normal mean of 2 measurements of 24-hour urinary free cortisol levels and cortisol level < 50 nmol/l after a 1 mg-overnight dexamethasone suppression test, normal testosterone in women (3) initial evaluation by a non-contrast and contrast CT at diagnosis (4) initial evaluation by 18FDG-PET (5) further follow-up in our department in the absence of surgery. Patients were not included when the CT which revealed the adrenal incidentaloma had been performed for the staging of a cancer or for the evaluation of secondary hypertension. The study was approved by the local ethical committee of Aix-Marseille University. All patients gave informed consent for the use of anonymous personal data extracted from their medical records for research purposes.
Dedicated adrenal CT imaging protocol
Every CT was performed on TOSHIBA Aquilion Prime (120 keV, 288 or 564 mAs, 0.6-mm slice thickness) with 3D reconstructions and were performed in our center before and after administration of iodinated contrast medium. The regions of interest (ROIs) were determined by using the widest area on an enhanced part of the lesion. The relative wash out was then determined by (Arteriel density - tardive density / Arterial density).
18F-FDG PET CT Imaging protocol
18 F-FDG (4 MBq/Kg) was administered intravenously after fasting for 6 hours and acquisition of imaging data was performed at approximately 60 minutes post-injection. Blood glucose test was performed prior to scanning to confirm that all patients were normoglycemic. Attenuation correction was obtained by transmission imaging with computed tomography. Reconstructions in the transaxial, coronal and sagittal planes were performed. A region of interest (ROI) was drawn on the primary tumor and on the VIII hepatic segment. Activity counts in the ROIs were normalized to injection doses per kilogram of patient body weight (maximum standardized uptake value: SUVmax). The SUVmax in the ROI on PET images was measured.
Imaging and biological follow-up strategies
Patients who were not operated after initial diagnosis were followed in our department, till delayed surgery or for at least 3 years after initial diagnosis if they were not operated. During this follow-up, imaging procedure was performed at 6 months, and then yearly: CT was systematically performed, while 18 F-FDG was performed at least once during the follow-up. Significant tumor growth was defined by a 10% increase of the largest diameter of the lesion. Hormonal workup identical to the initial one depicted previously was performed at 6 months and every year, or in case of appearance of clinical signs of hypersecretion or comorbidities such as hypertension or diabetes. Subclinical hypercortisolism was defined following the ESE/ENSAT guidelines, as being likely when the cortisol after 1 mg-overnight dexamethasone suppression test was between 51 and 138nmol/L (1.9-5.0ug/dL) and certain when superior to 138 nmol/L, associated with suppressed ACTH secretion and the absence of comorbidities usually associated with hypercortisolism (1).
Statistical analysis
Statistical analysis was performed using Prism 6 GraphPad Statistics. Continuous variables were expressed as means +SD and categorical variables were reported as count and percentages. All the tests were two-sided. For statistical comparisons of dichotomous data, we used the x2 test. Kaplan Meier estimates were performed to determine the risk of onset of hypersecretion during follow-up in patients not operated at first diagnosis. The statistical significance was defined as p<0.05 and with 95% confidence intervals.
RESULTS
81 patients (55.5% females, mean age 57.6 years) were included in this study (figure 1). Adrenal tumor size was between 4 and 6 cm in 66 patients (81.5%), and superior to 6 cm in 15 patients (18.5%). 44 patients had initial surgery, and 37 were followed, including 21 who were finally operated after a mean time of 19.6 +/- 21.7 after initial diagnosis. At last follow-up, 16 patients had not been operated after a mean time of 45.4 +/- 15.3 months after initial diagnosis (Figure 1).
Patients and tumor characteristics (table 1)
Among the 44 patients who had initial surgery, the investigator’s rationale to proceed to surgery was based on the tumor diameter in 17 (4.5%), and/or imaging characteristics in 36 (unenhanced CT > 10 in 20 (45.2%), PET 18FDG ratio > 1.5 in 16 (37.2%)), and/or patient’s choice in 19 (44.1%) cases. All the 15 patients who had a tumor larger than 6 cm were operated at diagnosis.
Among the 37 patients not operated at first diagnosis, 24 had a follow-up superior to 3 years (mean, 47 months; min, 36; max, 71), ie. 13 patients were operated in the first 3 years after initial diagnosis: reasons for surgery were: tumor growth in 75% (n=9) cases, and/or unenhanced CT > 10 in 33.3% (n=4) cases and/or hypersecretion in 38.4% (n=5) cases. Altogether, among the 65 operated patients (44 at diagnosis, and 21 during the follow-up), 13 (20%) had malignant lesions. The mean size of these malignant tumors was 55.9 +/- 12.5 mm. In the subgroup of tumors larger than 6 cm, 40% (n=6) were malignant (vs 14% in the subgroup of tumors between 4 and 6 cm; p=0.014). The pathological nature of these lesions was metastasis (n=3, including 2 from lung cancer and 1 of undetermined origin) and adrenocortical carcinoma (n=10), with a WEISS score of 4 (n=2), 5 (n=3), 6 (n=3) and 7 (n=2). DOI:10.4158/EP-2018-0616 c 2019 AACE
In contrast, 52 patients (80%) had benign lesions; 15 of them had a Weiss score of 1 (n=12) and 2 (n=3). Beside myelolipomas (n=2) and non-secreting pheochromocytomas (n=3 with PASS score of 0 or 1), 37 tumors were classified as adrenocortical adenomas with WEISS scores < 3. The mean size of these benign tumors was 48.4 +/- 7.8 mm versus 55.9 +/- 12.5 mm for malignant tumors (p=0.04)
Imaging characteristics and benign or malignant tumor
Among the 13 patients with a malignant tumor, 3 (23%) had unenhanced CT density < 10 UH. They all had adrenal carcinomas. Pathological analyses showed diffuse intracellular lipids in the 3 tumors, but no macroscopic fat. More in detail, the first patient had a homogeneous 81 mm lesion, with unenhanced 9 HU, relative wash out 37%, SUV ratio 1.7, SUV Max 4.75 (Figure 2). The second patient had a homogeneous 64 mm lesion with unenhanced 9 HU, relative wash out 45%, SUV ratio 1.7, SUV Max 4.5. The third patient had a homogeneous 61 mm lesion, with unenhanced 8 HU, relative wash out 40%, SUV ratio 1.9; SUV Max 5.7. Among these 13 patients, a total of 5 (38%) had a wash-out > 45%. In contrast, among the 52 patients with an operated benign tumor, 10 (19%) had spontaneous CT density > 10 UH and 2 (4%) had a wash-out < 45%. Altogether, unenhanced CT < 10 showed 85.6% (CI95%=54.5-98.1) sensitivity and 78.8% specificity (CI95%=65.3-88.9); a CT density of 19 gave 69.2% sensitivity (CI95%=38.5-90.9), and 98.1% specificity (CI95%=89.7-99.9) (p<0.0001)). A relative wash-out of 45% showed 61.5% (CI95%=31.6-88.1) sensitivity and 92.3% specificity (CI95%=81.4-97.4); a wash out of 41% gave 61.5% sensitivity (CI95%=31.5-86.1), and 96.1% specificity (CI95%=86.7-99.5) (p<0.0001).
Among the 13 patients with a malignant tumor, all had a 18F-FDG uptake ratio > 1.5. In contrast, among the 52 patients with a benign tumor, 6 (11.5%) had a 18F-FDG uptake ratio >
1.5, with 3 non-secreting pheochromocytomas (18F-FDG uptake ratio =1.9, 3.1, 2.4), 2 non- secreting adrenal adenomas, and 1 myelolipoma. A 18F-FDG uptake ratio of 1.5 had a sensitivity of 100% (CI95%=75.2-100) and a specificity of 92.3% (CI95%=81.4-97.8) (p<0.0001). The ROC curves for spontaneous CT density and 18F-FDG uptake ratio are depicted in additional figures 1 and 2.
In the whole cohort, 53 patients had initial unenhanced CT < 10, and wash out > 45%, and 18F- FDG uptake ratio < 1.5: 37 of them were operated, and all of them had a final diagnosis of benign lesion; of note, 20 of them were operated during the follow-up because of changes in size (n=13), CT features (n=5) and/or change in secretory status (n=2). None turned out to be malignant. The 16 remaining patients were still followed at last evaluation, and did not show any clinical imaging feature of a malignant tumor during the follow-up. Precise imaging characteristics of all the patients are depicted in table 2.
Secretory status during follow-up
37 patients were not operated initially, and were followed for a median period of 36 months (range, 4-71). Five of the 37 patients not operated after initial diagnosis (13.5%) showed changes in their secretory status during the follow-up (table 3). Four showed likely subclinical hypercortisolism. They all had abnormal overnight (cortisol range after the test, 70-94 nmol/l) and low dose dexamethasone suppression test (cortisol range after the test, 58-91 nmol/l), while urinary free cortisol was slightly increased (1.1 fold upper limit normal) in 2 patients. One patient had patent Cushing’s syndrome with weight gain, hypertension and hypokaliemia; hormonal workup showed suppressed ACTH, 1.7 fold upper limit normal 24-hour urinary free cortisol, and a cortisol level after 1 mg-overnight dexamethasone suppression test of 84 nmol/. Of note, only 2 patients showed increased size of the adrenal tumor at the time DOI:10.4158/EP-2018-0616 C 2019 AACE
hypersecretion was diagnosed. Mean time for hypersecretion appearance was 30 months (min, 16; max, 48). Kaplan Meier estimates of new onset of hypercortisolism in the 37 patients not operated at first diagnosis is depicted in figure 3. No increase of aldosteron, testosterone or metanephrins was observed. These 5 patients were all presenting reassuring initial imaging criteria with unenhanced CT < 10 and 18F-FDG uptake ratio <1.5. None had malignant lesion at pathology.
DISCUSSION
To our knowledge, we report for the first time a modern (18 F-FDG PET) and dedicated analysis of the characteristics and outcome (for those not operated) of large non-secreting adrenal masses, i.e. rare (only 81 cases among 1981 patients with adrenal diseases) clinical situations for which there is no clear management guidelines. We chose the 4 cm cut-off as Barzon et al. showed that the risk of malignancy increased in tumors larger than 4 cm (with a peak of 50% risk in tumors larger than 6 cm) (Barzon et al. 2003, Mege et al. 2014). The largest study ever reported on large adrenal tumors included 705 large adrenal tumors (at least 4 cm), including 472 which were incidental: they showed a proportion of 31% of malignant tumors in their cohort; specific data on the combined use of CT and 18FDG-PET to characterize these tumors were not provided. Except for this study, literature data are scarce, given the rarity of these large tumors: for instance, out of 449 patients analyzed for the outcome of adrenal tumors, Hong et al. suggested that the risk of malignancy increased when the size was > 3.4 cm, based on 16 patients (9).
Our data suggest that the imaging criteria of benignity reported in the ESE/ENSAT guidelines, and updated by a recent study of 18F-FDG PET/CT can also be applied to adrenal tumors larger than 4 cm, a point that was still under debate in these guidelines (1). In our cohort, unenhanced CT density < 19 was in favor of a benign lesion with 70% sensitivity and 98% specificity, with a PET 18FDG ratio > 1.5 gave 100% sensitivity and 92.3% specificity. The recent large Mayo Clinic Study gave 98% sensitivity and 64% specificity for the diagnosis of malignancy with an unenhanced CT attenuation at least equal to 20 HU, emphasizing the need for a further confirmatory test. Surprinsingly, in contrast with the study by Hong et al., and the study by Iniguez-Aritza, we identified 3 adrenal carcinomas, with homogeneous CT characteristics, and an attenuation below 10 HU (though very close, with 8-9 HU). The DOI:10.4158/EP-2018-0616
additional value of 18FDG PET was shown for at least 1 of our patient who presented with an adrenocortical carcinoma operated on the basis of the 18F-FDG uptake ratio, while CT characteristics were in favor of a benign lesion. Combination of both parameters was always found in benign tumors in our cohort, whatever the size: none of the tumors larger than 6 cm with spontaneous CT density < 10HU and 18F-FDG uptake ratio < 1.5 turned out to be malignant; this was also true in tumors between 4 and 6 cm. Other surgical studies reported the pathological analysis of adrenal tumors larger than 4 cm, but none of them depicted the value of the combination of CT and 18F-FDG PET/CT in the diagnosis of large adrenal masses. While the guidelines recommend to either perform an additional imaging, surgery or a new imaging after 6 months in uncertain adrenal masses (1), we suggest that both unenhanced CT and 18F-FDG PET/CT be systematically done in adrenal tumors larger than 4 cm. Of note, 18F- FDG PET/CT could also modify the surgical approach (adrenalectomy by endoscopy or large resection including kidney by an open surgery technique).
From an endocrine viewpoint, Morelli et al. focused on the risk of developing subclinical hypercortisolism: they reported that 14% of patients with normal initial hormonal workup and with an adenoma > 2.4 cm developed subclinical hypercortisolism during follow-up (median, 72 months), vs 3% when the size was < 2.4 cm (11). The risk of developing a clinically patent hypersecretion had been previously evidenced for tumors larger than 3 cm (12): however, this series of 64 patients was not including any patient with tumors larger than 4 cm. The prevalence of subclinical or patent hypercortisolism was 13% in our patients; however, our follow-up was inferior to the study by Morelli et al. It is thus likely, as shown by our Kaplan Meier curve, that the risk of developing hypersecretion is higher in tumors larger than 4 cm, and should thus lead to a regular follow-up of non-operated patients.
Our study is limited by its retrospective nature. However, all our patients were managed and followed based on the decisions of the same multidisciplinary expert team. The management of such patients can thus be considered homogeneous. Another limit is the relatively low number of patients, especially with tumors larger than 6 cm, and the fact that less than the half of our patients were not operated immediately. This is indeed a limit in terms of hormonal outcome of such tumors, but is a strength for our primary endpoint which was to determine the accuracy of imaging techniques in this specific group of tumors. This is why, given the rate of malignant tumor in size > 6 cm, we cannot recommend a follow-up even if imaging is reassuring: future collaborative studies with a large number of patients should be aimed at determining this specific point. For tumors between 4 and 6 cm, given the higher number of patients in our cohort, we consider that the association of reassuring unenhanced CT and 18F- FDG PET/CT might lead to a close follow-up rather than an immediate surgery, provided the decision is validated by an expert multidisciplinary team, also taking into account patients comorbidities, follow up constraints and patient’s choice between follow up (induced anxiety) and surgery (Figure 4).
To conclude, our data suggest that the accuracy of imaging modalities should probably change the paradigm of management of large adrenal masses with a possible switch in selected cases from surgery to follow-up. In this situation (large tumor, “benign-like” imaging findings), the risk of malignancy (ACC, retroperitoneal sarcoma, metastasis) should not be underestimated although not found in our series. It is therefore of main importance to perform additional studies including the recently introduced ex vivo metabolomics in order to provide a more personalized approach in patients with large adrenal masses. This also means that the management of these rare tumors of large size should still be discussed in expert multidisciplinary team meetings, regardless of the initial imaging findings and also taking into DOI:10.4158/EP-2018-0616 C 2019 AACE
account patients comorbidities. Finally, given the risk of developing subclinical or clinically patent hypercortisolism clinical and hormonal evaluation of cortisol hypersecretion should probably be done on a yearly basis in these patients. Further large prospective multicentre studies are therefore needed for defining an optimal algorithm.
Conflict of interest : All authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported Funding : This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
LEGEND TO TABLES AND FIGURES
Table 1: Patients features depending on tumor size. Apparent non functioning adenoma was defined by the lack of hypersecretion at last available evaluation. For hypersecretion during follow-up, data are based on the 37 patients who were not operated at first diagnosis. Subclinical hypercortisolism was defined following the ESE/ENSAT guidelines, as being likely when the cortisol after 1 mg-overnight dexamethasone suppression test was between 51 and 138nmol/L (1.9-5.0µg/dL) and certain when superior to 138 nmol/L, associated with suppressed ACTH secretion and the absence of comorbidities usually associated with hypercortisolism
Table 2: Patient’s final diagnosis depending on anatomical and radionuclide imaging evaluation at diagnosis.
Table 3: Features of patients with appearance of hypersecretion during follow up. RWO, relative wash-out; UFC, urinary free cortisol (ULN, upper limit normal); ODST, overnight dexamethasone suppression test; LDDST, low dose dexamethasone suppression test.
Figure 1: Flow-chart of the study.
Figure 2: Example of adrenal CT with unattenuated density < 10 HU. Final diagnosis was adrenal carcinoma.
Figure 3: Kaplan Meier curve showing the percent of patients not operated at first diagnosis, without hypersecretion during the follow-up. Median follow-up in these patients was 36 months. Dotted line, 95% confidence interval.
Figure 4: Suggested algorithm for management of large adrenal tumors.
Additional figure 1: ROC curve for unenhanced CT and malignancy.
Additional figure 2: ROC curve for 18 F-FDG PET ratio and malignancy.
REFERENCES
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DOI:10.4158/EP-2018-0616 C 2019 AACE
| total patients (n=81) | 4<size<6cm (n=66) | >6cm (n=15) | p value | |
|---|---|---|---|---|
| female n(%) | 45 (55.5) | 36 (59.1) | 6 (40) | 0.051 |
| age | 57.6 | 57.8 | 56.5 | 0.44 |
| follow-up >3years, n(%) | 25 (30.8) | 30 (37.8) | 0 (0) | 0.001 |
| malignant, n(%) | 13 (16) | 7 (10.6) | 6 (40) | 0.02 |
| anatomical and | ||||
| radionuclide imaging features: | ||||
| Mean tumor diameter | 0.03 | |||
| (mm) | 48.8 | 45.5 | 62.7 | |
| Unenhanced CT density | 0.04 | |||
| <10 HU, n(%) | 61 (75.3) | 52 (78.7) | 9 (60) | |
| wash-out >45% | 71 (87.6) | 60 (90.9) | 11 (73.3) | 0.06 |
| Uptake ratio <1.5 | 64 (79) | 55 (83.3) | 8 (53.3) | 0.01 |
| biological features: | ||||
| Hypersecretion during | ||||
| follow-up* | 5 (13.5) | 5 (13.5) | NA* | NA* |
| final diagnosis: | ||||
| apparent non-functioning | ||||
| adrenal adenoma | 42 (51.9) | 33 (50) | 9 (60) | 0.1 |
| adrenocortical cancer | 10 (12.3) | 6 (9.1) | 4 (26.6) | 0.03 |
| subclinical cushing | ||||
| syndrome | 4 (4.9) | 4 (6.1) | NA* | NA* |
| pheochromocytoma | 3 (3.7) | 3 (4.5) | 0 (0) | 0.2 |
| metastatic cancer | 3 (3.7) | 1 (1.5) | 2 (13.3) | 0.03 |
| myelolipoma | 2 (2.4) | 2 (3) | 0 (0) | 0.13 |
| Adenoma with Cushing's | ||||
| syndrome | 1 (1.2) | 1 (1.5) | NA* | NA* |
| management strategy: | ||||
| surgery | 65 (80.2) | 50 (75.7) | 15 (100) | 0.03 |
| follow up only | 16 | 0.02 | ||
| (19.9) | 16 (24.3) | 0 (0) | ||
| total patients (n=81) | CT<10 AND wash- out>45 AND SUVratio<1.5 (n=55) | CT>10 and/or wash- out<45 and/or SUVratio>1.5 (n=29) | p value | |
|---|---|---|---|---|
| female n(%) | 45 (55.5) | 29 (51.7) | 16 (57.1) | 0.5 |
| age | 57.6 | 57.6 | 57.5 | 0.7 |
| follow-up >3years, | 0.01 | |||
| n(%) | 25 (30.8) | 24 (42.8) | 1 (3.5) | |
| tumor diameter (mm) | 48.8 | 46.6 | 52.7 | 0.07 |
| malignant | 13 (16) | 0 (0) | 13 (44.8) | 0.001 |
| final diagnosis: apparent | 0.06 | |||
| nonfunctioning | ||||
| adenoma | 42 (51.9) | 31 (55.3) | 12 (42.8) | |
| adrenocortical cancer | 10 (12.3) | 0 (0) | 10 (34.4) | 0.001 |
| subclinical Cushing | ||||
| syndrome (adenoma) | 4 (4.9) | 4 (7.1) | 0 (0) | 0.02 |
| pheochromocytoma | 3 (3.7) | 0 (0) | 3 (10.7) | 0.01 |
| metastatic cancer | 3 (3.7) | 0 (0) | 3 (10.7) | 0.01 |
| myelolipoma | 2 (2.4) | 0 (0) | 2 (7.1) | 0.02 |
| Cushing's syndrome | ||||
| (adenoma) | 1 (1.2) | 0 (0) | 1 (3.5) | 0.15 |
| follow up | 16 (19.9) | 16 (28.9) | 0 (0) | 0.01 |
Table 3: Features of patients with appearance of biological abnormalities during follow up
| Patient 1 | Patient 2 | Patient 3 | Patient 4 | Patient 5 | |
|---|---|---|---|---|---|
| Final diagnosis | subclinical Cushing's syndrome | subclinical Cushing's syndrome | subclinical Cushing's syndrome | subclinical Cushing's syndrome | Cushing's syndrome |
| Size (mm) | 40 | 45 | 42 | 46 | 46 |
| CT density (HU) | 7 | 5 | -5 | 1 | 3 |
| RWO (%) | 62 | 81 | 84 | 84 | 64 |
| SUV ratio | 1.1 | 1.1 | <1 | <1 | 1.2 |
| % size increase | 10 | 0 | 0 | 0 | 15,2 |
| reasons for | hormonal secretion + size increase | hormonal secretion | hormonal secretion | hormonal secretion | hormonal secretion + size increase |
| surgery | |||||
| mean follow-up | |||||
| (months) | 36 | 41 | 16 | 40 | 16 |
| UFC (x ULN) | 1.1 | 0.7 | 1.1 | 0.7 | 0.9 |
| ODST (nmol/L) | 94 | 84 | 94 | 70 | 84 |
| LDDST (nmol/L) | 91 | 58 | 61 | 61 | 70 |
| ACTH (pg/ml) | 1 | 2 | 1 | 2 | 1 |
| clinical | |||||
| hypercortisolism | no | no | no | no | yes |
1981 adrenal tumors
81 Non secreting adrenal incidentalomas equal or higher to 4 cm
Follow-up only
Surgery
N=16
N=65
Mean follow-up 45.4+/-15.3 months
Initial surgery
Delayed surgery
N=44
N=21
13 Malignant
Mean follow-up 19.6 +/- 21.7 months
Figure 1
No malignancy
Percent patients without hypersecretion
100
50
0
0
20
40
60
80
mean follow-up (mth)
Non secreting large adrenal incidentaloma Unenhanced CT < 10 HU and 18 F FDG PET-CT ratio < 1.5
< 40 mm
40-60 mm
> 60 mm
ESE/ENSAT guidelines
Intermediate risk of malignancy
High risk of malignancy
Expert center Pluridisciplinary team Consider follow-up Hormonal screening yearly Imaging at 3, 6 and 12 months and then yearly
Expert center Pluridisciplinary team Consider surgery
Sensitivity%
100
50
0
0
50
100
100% - Specificity%
Additional figure 1
Sensitivity%
100
50
0
0
50
100
100% - Specificity%
Additional figure 2