Case Report

The Addition of 18F-FDG PET/CT in the Assessment of Indeterminate Adrenal Incidentalomas

Scott Assen1, Denise Chan2 and Janice L Pasieka1*
1Department of Surgery, University of Calgary, Canada
2Department of Radiology, University of Calgary, Canada


*Corresponding author: Janice L. Pasieka, Clinical Professor of Surgery and Oncology, Section of General Surgery and Surgical Oncology, University of Calgary, Cumming School of Medicine, 1403 29th Street NW, Calgary Alberta, Canada


Published: 05 Jan, 2017
Cite this article as: Assen S, Chan D, Pasieka JL. The Addition of 18F-FDG PET/CT in the Assessment of Indeterminate Adrenal Incidentalomas. Clin Oncol. 2017; 2: 1180.

Abstract

Adrenal masses are common and their management has been the subject of some scrutiny. Initial workup consists of history and physical examination, biochemical evaluation, and imaging, typically using CT or MRI. Some lesions are convincingly benign-appearing on initial imaging and their management typically consists of routine follow-up or laparoscopic resection if the lesion is functional. Others possess imaging characteristics concerning for adrenal cortical carcinoma, such as size >4 cm, heterogeneity, central necrosis or calcifications. For lesions with one or more of these characteristics, the use of 18F-FDG PET/CT is currently unclear in the literature. We propose a novel algorithm utilizing PET/CT for the assessment of indeterminate adrenal masses. We recommend using PET/CT to distinguish lesions that can followed from those that can be resected endoscopic ally and those for which an open surgical approach should be used.

Introduction

Adrenal masses represent one of the most common incidental findings. The incidence of clinically unapparent adrenal masses is estimated to be 2.0% on autopsy studies [1]. With the widespread use of cross-sectional imaging, these lesions are found frequently, and are found with a prevalence of 3-10% of imaging done for non-adrenal causes [1,2]. The differential diagnosis for adrenal masses is broad, but most lesions (75%) are found to be non-functioning adenomas [1]. Other causes include functioning cortical adenomas that secrete cortisol or aldosterone, pheochromocytomas, myelolipomas, cysts, ganglioneuromas, metastases and rarely adrenal cortical carcinomas.
Adrenal Cortical Carcinoma (ACC) is a rare clinical entity with an estimated prevalence of 4-12 per million adults [3]. The prevalence for ACC is size-dependent, as only 2% of adrenal lesions less than 4 cm are ACC, 6% of lesions between 4.1-6 cm are ACC, and ACC is found in 25% of adrenal lesions greater than 6 cm [4]. A broad spectrum of age ranges is affected by this disease but the average age at presentation in the adult population is 40 to 50 years [5]. Females are affected more than males, at 58.6% vs. 41.4% [6].
A number of algorithms and approaches to incidental adrenal masses and adrenal cortical carcinoma have been proposed, including guidelines from the National Institutes of Health, the European Society for Medical Oncology, the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons, the American College of Radiology, the European Society of Endocrinology, and others [1,4,7-11]. For patients with a history of known malignancy, Positron Emission Tomography (PET) or PET/CT using the radiopharmaceutical 2-deoxy-2- [fluorine-18]fluoro-D-glucose (18F-FDG) is typically recommended to distinguish between benign lesions and metastases [1,4,8-12]. The role of 18F-FDG PET/CT in patients without a history of malignancy is currently unclear in the literature. Recommendations range from avoiding its use to considering it a useful tool for distinguishing benign from malignant disease for radiographically indeterminate lesions [1,8,10,11,13]. Recent experience at our center with three complex incidentalomas has provided us with some insight into the value of PET/CT in the surgical planning of these lesions. We propose a novel algorithm for the workup of incidental adrenal masses that uses 18F-FDG PET/CT to confidently classify otherwise indeterminate lesions, allowing the surgeon to appropriately select the surgical approach, and for the non-operative management of benign tumors that may otherwise have been resected.

Figure 1

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Figure 1
Axial contrast-enhanced CT image of Patient A, who was found to have an incidental 8.3 cm x 7.9 cm mass arising from the right adrenal gland with heterogeneity and calcifications.

Figure 2

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Figure 2
Coronal contrast-enhanced CT image of Patient A, who was found to have an incidental 8 x 8 cm mass arising from the right adrenal gland with heterogeneity and calcifications.

Figure 3

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Figure 3
Coronal 18F-FDG PET, PET/CT, and CT of Patient A's right adrenal mass. Note the metabolic activity within the mass less than background liver activity.

Figure 4

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Figure 4
Axial 18F-FDG PET/CT of Patient A's right adrenal mass. Note the metabolic activity within the mass less than background liver activity.

Cases

Recent experiences at our centre have prompted the question of whether to expand the role of PET/CT in evaluating incidental adrenal masses. Below are three representative cases.
Patient A
Patient A is a 67-year-old male who was found to have a 9.7 cm right adrenal mass on ultrasound performed as part of the evaluation for a new diagnosis of congestive heart failure. This prompted a CT scan which revealed an 8.3 cm x 7.9 cm mass arising from the right adrenal gland and in close proximity to the liver and IVC (Figure 1,2). The lesion was a heterogeneously enhancing mass with central cystic changes and calcification. There was no definite macroscopic fat. Clinically, the patient had morbid central obesity and was hypertensive, on two antihypertensive agents. Biochemical evaluation revealed an elevated 24-hour urinary cortisol and a lack of suppression found on overnight dexamethasone suppression testing. The findings were concerning for an ACC. An 18F-FDG PET/CT was obtained to clinically stage the patient prior to surgical resection of this mass. The mass was found to have low grade metabolic activity less than liver background activity (Figures 3,4) which favoured a benign pathology.
Given the secretory nature of the tumor, resection was warranted, and an open adrenalectomy was pursued given the size and features on imaging that were suspicious for ACC. The final pathology demonstrated a benign adrenocortical adenoma with areas of old hemorrhage and cystic degeneration.
Patient B
Patient B is a 43-year-old man who was found to have an incidental 14 cm left upper quadrant mass found on ultrasound performed to investigate for biliary colic. Subsequent CT scan revealed a 20 x 15 x 13 cm mass arising from the left adrenal gland (Figures 5,6). This lesion was heterogeneous in density and enhanced with irregular borders and areas of calcification. On MRI, the mass enhanced heterogeneously with no evidence of intracellular lipid or macroscopic fat (Figure 7). The patient was asymptomatic with no features suggestive of hormonal excess and his only physical examination findings were a palpable left upper quadrant mass and some mild right upper quadrant tenderness. Biochemical evaluation revealed a lack of suppression on overnight dexamethasone suppression testing despite a normal 24-hour urinary cortisol level, as well as an elevated DHEA-S level. Once again, a PET/CT was obtained to look for evidence of distant metastatic disease prior to surgical intervention. Unlike the first patient, this mass was intensely FDG avid greater than liver background on the 18F-FDG PET/CT highly suggestive of ACC (Figures 8,9).
An open en-bloc left adrenalectomy, nephrectomy and resection of the retroperitoneal lymph nodes was performed. Final pathology demonstrated adrenal cortical carcinoma with a Ki67 of 2%, few mitoses and negative lymph nodes. Lymphovascular invasion and microscopic extension into adjacent adipose tissue was found.
Patient C
Patient C is a 50-year-old female who was found to have a 6 cm right adrenal mass on a CT scan performed for abdominal discomfort and bloating. There were no other symptoms aside from a weight gain of 8-10 lbs over one year. The lesion measured greater than 20 Hounsfield units on a non-contrast CT and enhanced heterogeneously on a contrast CT (Figure 10). The patient’s 24-hour urine cortisol was elevated, and overnight dexamethasone suppression testing revealed a lack of suppression. DHEA-S level was also elevated. On MRI, the mass was heterogeneous and did not have evidence for microscopic or macroscopic fat to confirm a benign etiology and was therefore indeterminate (Figures 11-14). To help further define this intermediate lesion, a PET/CT was obtained. The mass showed intense metabolic activity on 18F-FDG PET/CT greater than liver background level, suggestive of ACC (Figures 15,16).
Although this lesion was amenable to a laparoscopic resection, the PET/CT was concerning for ACC, so an open an adrenalectomy was performed. Final pathology revealed a 15 cm ACC, with tumor extension into the margins of the specimen including the adrenal vein and the kidney margin. Within the tumor, multifocal necrosis and 24 mitoses per 50 high power fields were found.
Given the similarity of all three cases with respect to imaging findings using conventional modalities, the utilization of PET/CT could have helped to guide the surgical approach. A case can be made for the utilization of PET/CT in differentiating benign from malignant adrenal masses. The exclusion of malignancy could have allowed for the utilization of a laparoscopic approach in the first case; appropriately staged and solidified the aggressive open approach in the second case, and helped focus to select the appropriate resection of a very aggressive ACC in the third patient. It is also conceivable to consider a non-operative approach in small non-functional indeterminate adrenal lesions that are shown to be benign on PET/CT.

Figure 5

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Figure 5
Axial contrast-enhanced CT of Patient B, who was found to have an incidental left adrenal mass. The mass is 20 x 15 x 13 cm and heterogeneous with central hypoattentuation and calcification.

Figure 6

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Figure 6
Coronal CT of Patient B, who was found to have an incidental left adrenal mass. The mass is 20 x 15 x 13 cm and heterogeneous.

Figure 7

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Figure 3
Axial MRI T1-weighted post gadolinium image of Patient B, who was found to have an incidental left adrenal mass. The mass is 20 x 15 x 13 cm and has heterogeneous enhancement with central cystic change. No evidence of macroscopic or microscopic fat on other MRI sequences (not shown).

Figure 8

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Figure 8
Coronal 18F-FDG PET, PET/CT, and CT of Patient B's left adrenal mass. Note the intense FDG avidity greater than liver background.

Figure 9

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Figure 9
Axial 18F-FDG PET/CT of Patient B's left adrenal mass. Note the intense FDG avidity greater than liver background.

Figure 10

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Figure 10
Axial unenhanced CT image of Patient C, who was found to have a mass arising from the right adrenal gland with heterogeneity on CT performed for abdominal discomfort and bloating. The density of this mass measured greater than 20 HU.

18F-FDG PET/CT

Positron Emission Tomography (PET) using 2-deoxy-2- [fluorine-18]fluoro-D-glucose (FDG) is an imaging modality that leverages the uptake of fluoride-tagged glucose molecules as a surrogate of metabolic activity. It is thus an excellent marker for identifying areas of intense hypermetabolism such as metastases in highly metabolically active cancers. Potential pitfalls of PET include its inability to pick up small lesions (less than 1 cm), cancers with a low metabolic rate, and cancers where nearby physiologic uptake such as the brain or the bladder will obfuscate results [21]. It is frequently combined with synchronous computed tomography, improving its anatomic localization (PET/CT). There is a five percent false positive rate with increased FDG uptake present in certain processes such as sarcoidosis, infection, some adrenal adenomas and adrenal cortical hyperplasia [22]. The use of 18F-FDG PET/CT in the evaluation of incidental adrenal masses is evolving. In the setting of patients with a prior history of cancer, 18F-FDG PET/CT is relatively well-established as a method for identifying metastases, including in the adrenals [1,4,8-12,21]. Conversely, the use of 18F-FDG PET/CT in evaluating adrenal masses in patients without a history of cancer is less clear. There have been several prospective studies attempting to clarify this issue. In studies using histopathology as a gold standard, the sensitivity of 18F-FDG PET/CT ranges from 97% to 100%, with a specificity of 83% to 93% [13,17,23,24]. These values, however, reflect cut-off values selected for the maximal standardized uptake value of the lesion (SUVmax) or the adrenal to liver SUVmax ratio. Area under the curve for receiver operator curves (ROC) for these values range from 0.91 to 0.99 for both values [17,25]. Qualitative analysis is also frequently used in current practice, and in a meta-analysis of the use of 18F-FDG PET/CT for all adrenal masses, its performance was also found to be excellent with a sensitivity of 96% and a specificity of 91% [25]. In this same study, however, the adrenal to liver SUVmax ratio was a better discriminator, with a sensitivity of 100% and a specificity of 92% [25].

Table 1

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Table 1
Benign v/s indeterminate/malignant features on various imaging modalities.

Figure 11

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Figure 11
Axial post-gadolinium T1-weighted MRI image of patient C, showing large heterogeneously enhancing right adrenal mass.

Figure 12

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Figure 12
Axial T2-weighted MRI image of patient C, showing large right adrenal mass with heterogeneous signal intensity and no macroscopic fat.

Figure 13

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Figure 13
Axial MRI in-phase image of patient C, showing large right adrenal mass.

Figure 14

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Figure 14
Axial MRI out-of-phase image of patient C, showing no loss of signal to confirm intracellular fat in right adrenal mass.

Figure 15

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Figure 15
Coronal 18F-FDG PET, PET/CT, and CT of Patient C's right adrenal mass. Note the intense FDG avidity greater than liver background.

Figure 16

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Figure 16
Axial 18F-FDG PET, PET/CT, and CT of Patient C's right adrenal mass. Note the intense FDG avidity greater than liver background.

Figure 17

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Figure 17
Algorithm for the management of patients with indeterminate adrenal masses. Indeterminate masses include those with any of: > 10 Hounsfield units on CT, lack of changes to suggest lipid rich adenoma on CT or MRI, contrast agent washout less than 50% on CT, heterogeneity, calcifications, or irregular borders.

Clinical Application

Currently, the recommendation for adrenal lesions suspicious for ACC is an open en-bloc resection as opposed to endoscopic adrenalectomy [4,7,8,10,11]. For benign adrenal lesions endoscopic adrenalectomy is recommended given the reduced morbidity and hospital length of stay. [26-29]. When there is a strong suspicion for ACC or metastatic cancer, 18F-FDG PET/CT should be performed to appropriately stage the patient prior to any surgical intervention. We propose however the selective use of PET/CT for indeterminate adrenal lesions (Figure 17).
The utility of PET/CT must however be balanced with its cost and its accessibility. At our institution, the approximate cost of an 18F-FDG PET/CT is $1400-1600 CAD. For comparison, an MRI for an adrenal mass is approximately $700 CAD for an enhanced study, and a CT for an adrenal mass is $250 for a non-contrast scan. Because of this discrepancy in cost and accessibility of some of these modalities throughout the world, the judicious use of PET/CT in situations where it can positively affect patient care and when it can result in cost and resource savings elsewhere is important. Even lesions with concerning features on imaging (size >4 cm, heterogeneity, calcifications, and irregular borders) but low FDG uptake are much less likely to be malignant, and as such an endoscopic resection could be considered. Therefore, the decision to use PET/CT should be a multidisciplinary decision and only undertaken when it may change the surgical approach or the decision to operate at all.

References

  1. Terzolo M, Stigliano A, Chiodini I, Loli P, Furlani L, Arnaldi G, et al. AME Position Statement on adrenal incidentaloma. Eur J Endocrinol. 2011; 164: 851-870.
  2. Androulakis II, Kaltsas G, Piaditis G, Grossman AB. The clinical significance of adrenal incidentalomas. Eur J Clin Invest. 2011; 41: 552-560.
  3. Grumbach MM. Management of the Clinically Inapparent Adrenal Mass (“Incidentaloma”). Ann Intern Med. 2003; 138: 424.
  4. Zeiger M, Thompson G, Duh Q-Y, Hamrahian A, Angelos P, Elaraj D, et al. American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the management of adrenal incidentalomas. Endocr Pract. 2009; 15: 1-20.
  5. Brennan MF. Adrenocortical carcinoma. CA Cancer J Clin. 1987; 37: 348-3465.
  6. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer. 1993; 72: 3145-3155.
  7. Donald CJ, Overhage JM, Barnes M, Schadow G, Blevins L, Dexter PR, et al. NIH State-of-the-Science Statement on Management of the Clinically Inapparent Adrenal Mass (“Incidentaloma”). Health Aff (Millwood). 2005; 24: 1214-1220.
  8. Berruti A, Baudin E, Gelderblom H, Haak HR, Porpiglia F, Fassnacht M, et al. Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012; 23: 131-138.
  9. Choyke PL. ACR Appropriateness Criteria® on Incidentally Discovered Adrenal Mass. J Am Coll Radiol. 2006; 3: 498-504.
  10. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016; 175: 1-34.
  11. Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer. 2005; 12: 667-680.
  12. Garrett RW, Nepute JC, Hayek ME, Albert SG. Adrenal Incidentalomas: Clinical Controversies and Modified Recommendations. Am J Roentgenol. 2016; 206: 1170-1178.
  13. Groussin L, Bonardel G, Silvéra S, Tissier F, Coste J, Abiven G, et al. 18F-Fluorodeoxyglucose Positron Emission Tomography for the Diagnosis of Adrenocortical Tumors: A Prospective Study in 77 Operated Patients. J Clin Endocrinol Metab. 2009; 94: 1713-1722.
  14. Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. Am J Roentgenol. 1998; 171: 201-204.
  15. Angeli A, Osella G, Ali A, Terzolo M. Adrenal Incidentaloma: An Overview of Clinical and Epidemiological Data from the National Italian Study Group. Horm Res. 1997; 47: 279-283.
  16. Pantalone KM, Gopan T, Remer EM, Faiman C, Loachimescu AG, Levin HS, et al. Change in Adrenal Mass Size as a Predictor of a Malignant Tumor. Endocr Pract. 2010; 16: 577-587.
  17. Launay N, Silvera S, Tenenbaum F, Groussin L, Tissier F, Audureau E, et al. Value of 18-F-FDG PET/CT and CT in the Diagnosis of Indeterminate Adrenal Masses. Int J Endocrinol. 2015; 2015: 1-8.
  18. Mayo-Smith WW, Boland GW, Noto RB, Lee MJ. State-of-the-Art Adrenal Imaging. Radio Graphics. 2001; 21: 995-1012.
  19. Terzolo M, Bovio S, Reimondo G, Pia A, Osella G, Borretta G, et al. Subclinical Cushing’s Syndrome in Adrenal Incidentalomas. Endocrinol Metab Clin North Am. 2005; 34: 423-439.
  20. Kopetschke R, Slisko M, Kilisli A, Tuschy U, Wallaschofski H, Fassnacht M, et al. Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma. Eur J Endocrinol. 2009; 161: 355-361.
  21. Almuhaideb A, Papathanasiou N, Bomanji J. 18F-FDG PET/CT Imaging In Oncology. Ann Saudi Med. 2011; 31: 3-13.
  22. Blake MA, Cronin CG, Boland GW. Adrenal Imaging. Am J Roentgenol. 2010; 194: 1450-1460.
  23. Maurea S, Mainolfi C, Bazzicalupo L, Panico MR, Imparato C, Alfano B, et al. Imaging of adrenal tumors using FDG PET: comparison of benign and malignant lesions. Am J Roentgenol. 1999; 173: 25-29.
  24. Zettinig G, Mitterhauser M, Wadsak W, Becherer A, Pirich C, Vierhapper H, et al. Positron emission tomography imaging of adrenal masses: 18F-fluorodeoxyglucose and the 11β-hydroxylase tracer 11C-metomidate. Eur J Nucl Med Mol Imaging. 2004; 31: 1224-1230.
  25. Boland GWL, Dwamena BA, Jagtiani Sangwaiya M, Goehler AG, Blake MA, Hahn PF, et al. Characterization of Adrenal Masses by Using FDG PET: A Systematic Review and Meta-Analysis of Diagnostic Test Performance. Radiology. 2011; 259: 117-126.
  26. Gagner M, Lacroix A, Prinz RA, Bolte E, Albala D, Potvin C, et al. Early experience with laparoscopic approach for adrenalectomy. Surg-St LOUIS-. 1993; 114: 1120-1120.
  27. Fletcher D, Beiles C, Hardy KJ. Laparoscopic adrenalectomy. Aust N Z J Surg. 1994; 64: 427-430.
  28. Go H, Takeda M, Imai T, Komeyama T, Nishiyama T, Morishita H. Laparoscopic adrenalectomy for Cushing’s syndrome: comparison with primary aldosteronism. Surgery. 1995; 117: 11-17.
  29. Schell SR, Talamini MA, Udelsman R. Laparoscopic adrenalectomy for nonmalignant disease: improved safety, morbidity, and cost-effectiveness. Surg Endosc. 2014; 13: 30-34.