Adrenal Incidentalomas: Risk of Adrenocortical Carcinoma and Clinical Outcomes
CHRISTINE J. O’NEILL, MBBS(Hons), FRACS,1 ANDREW SPENCE,1+ BARNEY LOGAN,1+ JAMES W. SULIBURK, MD,1 PATSY S. SOON, PhD, FRACS,2 DIANA L. LEAROYD, PhD, FRACP, STAN B. SIDHU, PhD, FRACS,1,2 AND MARK S. SYWAK, MMed(ClinEpi) FRACS1*
1 University of Sydney Endocrine Surgical Unit, St. Leonards, New South Wales, Australia 2Cancer Genetics, Kolling Institute for Medical Research, University of Sydney, Sydney, Australia
3 Department of Endocrinology, Royal North Shore Hospital, St. Leonards, New South Wales, Australia
3
Introduction: The number of incidentally discovered adrenal lesions is increasing due to the widespread use of abdominal imaging. Although most incidentalomas are benign, larger suspicious lesions will require adrenalectomy. The aim of this study is to determine the risk of malignancy in patients undergoing surgery for adrenal incidentaloma; and to compare clinical outcomes in those with adrenocortical carcinoma (ACC) based on the mode of presentation.
Methods: A retrospective study of consecutive patients who underwent adrenalectomy between 1995 and 2008 was performed. Data were retrieved from a prospectively maintained adrenal tumor database. Those with adrenal incidentaloma were selected and histopathology reviewed. All patients with ACC (presenting with symptoms or incidentally) during the same time period were identified and clinical outcomes compared. Results: Adrenalectomy was performed in 274 patients of whom 73 (27%) were characterized pre-operatively as incidentaloma. Benign, non- functioning adrenocortical adenoma was the most common histopathological finding (46 patients, 63%). There was a trend (P=0.08) towards increased survival amongst the seven patients with ACC presenting incidentally compared to the nine patients with symptomatic ACC. Conclusions: Adrenal incidentalomas have a small but important risk of malignancy. ACC presenting as incidentaloma appear to have a more favorable prognosis than symptomatic or functioning ACC.
J. Surg. Oncol. 2010;102:450-453. @ 2010 Wiley-Liss, Inc.
KEY WORDS: adrenalectomy; adrenocortical adenoma; adrenocortical carcinoma; incidental findings; pathology; surgical
INTRODUCTION
Adrenal incidentalomas are adrenal masses detected on abdominal imaging performed for indications other than the investigation of adrenal disease [1,2]. As both the quality and frequency of abdominal imaging rises, adrenal incidentalomas are becoming an increasingly prevalent clinical problem [3,4]. Prevalence is estimated at up to 4.4% in computerized tomography (CT) and 6% in autopsy series [3,5,6].
All adrenal incidentalomas should be investigated with biochemical screening to exclude adrenal hormone hypersecretion. The majority of patients will have small, non-secretory lesions without suspicious imaging features and will not require intervention [1,4,7,8]. Surgery should be considered for those with functioning lesions or those with non-functional lesions larger than 4 cm in diameter or with features suspicious for malignancy on CT [1,6,9]. In previous published series examining the histopathology of patients who undergo adrenalectomy for incidentaloma, the most common histopathological diagnosis is of a benign non-functioning adrenocortical adenoma [4]. Adrenocortical carcinomas (ACC) are rare [6,10].
Laparoscopic adrenalectomy is now widely accepted as the procedure of choice for benign adrenal lesions [11,12]. The aim of this study is to determine the risk of malignancy in a contemporary series of adrenal incidentalomas and to report the clinical outcomes of those with ACC presenting as incidentaloma against those with ACC presenting with a symptomatic tumor.
METHODS
A retrospective study of consecutive patients who underwent adrenalectomy between January 1995 and December 2008 was performed. Information was retrieved from a prospectively maintained
adrenal tumor database. Data retrieved included patient demographics, pre-operative diagnosis, operative approach, histopathological diag- nosis, and clinical outcome. Where necessary, patient’s medical history and histopathological reports were reviewed.
Patients were classified as having an adrenal incidentaloma when abdominal imaging was performed for indications unrelated to adrenal disease. Patients excluded from the diagnosis of adrenal incidentaloma included those with clinical symptoms relevant to the adrenal mass or those with biochemical results indicating abnormal adrenal function prior to initial radiological investigation. Histopathology results of those with incidentaloma were reviewed.
In addition to assessing the risk of malignancy in those with incidentaloma, and in order to assess prognosis, patients with ACC discovered incidentally were compared to patients presenting with clinically apparent ACC over the same 14-year time period. These patients were identified from the same adrenal tumor database and patient demographics, tumor characteristics and clinical outcomes evaluated.
This work was presented in an earlier form at the Royal Australasian College of Surgeons Annual Scientific Congress, Brisbane, May 2009. Medical student.
*Correspondence to: Dr. Mark S. Sywak, MMed(ClinEpi) FRACS, University of Sydney Endocrine Surgical Unit, 202/69 Christie St, St. Leonards, NSW 2065, Australia. Fax: 02-9437-1732. E-mail: marksywak@nebsc.com.au
Received 25 September 2009; Accepted 9 February 2010 DOI 10.1002/jso.21553
Published online 23 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
@ 2010 Wiley-Liss, Inc.
| Pathological diagnosis | Number (total 73) | Frequency (%) |
|---|---|---|
| Adrenocortical adenoma | ||
| Non-functioning | 46 | 63 |
| Subclinical Cushing's syndrome | 2 | 3 |
| Hyperaldosteronism | 1 | 1 |
| Adrenocortical carcinoma | 7 | 10 |
| Phaeochromocytoma | 2 | 3 |
| Adrenal cyst | 4 | 5 |
| Adrenal nodular hyperplasia | 1 | 1 |
| Myelolipoma | 2 | 3 |
| Ganglioneuroma | 2 | 3 |
| Adrenal hemorrhage | 1 | 1 |
| Other (non-adrenal tissue) | 5 | 7 |
Statistical analysis was performed using SPSS Software (Version 17.0, SPSS, Inc., Chicago, IL). Patient demographics were compared using the students t-test and tumor characteristics with the Mann-Whitney U-test. Categorical variables were compared using the Fisher’s exact test. Survival outcomes were analyzed using the Kaplan-Meier methods. Significance was set at P <0.05.
RESULTS
Over the 14-year study period, 274 patients underwent adrenalect- omy. The most common indications for adrenalectomy were hyperaldosteronism (85 patients, 31%), incidentaloma (73 patients, 27%), and pheochromocytoma (61 patients, 23%). Overall, 228 (83%) patients underwent laparoscopic adrenalectomy with 8 (4%) conver- sions to an open procedure. Indications for primary open adrenalect- omy in the remaining 46 patients included large lesions, known ACC and the need for a concurrent resection (nephrectomy, pancreatectomy, colectomy).
The histopathological diagnoses of the 73 patients with adrenal incidentaloma are summarized in Table I. Benign, non-functioning adrenocortical adenoma was the most common pathological finding (46 patients, 63%). Other benign diagnoses included myelolipoma, ganglioneuroma, adrenal cyst, adrenal nodular hyperplasia and adrenal hemorrhage. Five (7%) patients with adrenal incidentaloma had functional tumors identified during pre-operative investigation. This included two patients with phaeochromocytoma, two patients with sub-clinical Cushing’s syndrome, and one patient with hyperaldoster- onism. Adrenocortical carcinoma was diagnosed in seven (10%) patients in the incidentaloma group.
Over the 14-year study period there were a total of 16 patients diagnosed with ACC including the seven in the incidentaloma group and nine patients who presented with symptomatic ACC (Table II). Five of the patients with incidental ACC underwent laparoscopic resection (with 1 conversion due to high suspicion of malignancy)
compared with two laparoscopic resections amongst the nine patients with symptomatic ACC. Patient age and pre-operative adrenal size were not significantly different between the groups, however, Weiss score was significantly higher (P=0.03) in those with symptomatic ACC (median 5) compared to those with an incidental presentation (median 3). Of the nine patients with clinically apparent ACC, seven presented with functioning tumors and two had widespread disease (metastases to retroperitoneal nodes and liver) at the time of initial operation. Seven of the nine patients in this group are deceased, with a median survival of 24.5 months (range 3-56 months). The remaining two patients with symptomatic ACC remain alive and disease free at 18 and 29 months post-operatively. In contrast, of the seven patients with ACC that presented as adrenal incidentaloma, none had functioning tumors and at a median follow-up of 34 months (range 6-60 months), there have been two deaths, one due to ACC and the other due to an unrelated malignancy.
Kaplan-Meier survival analysis comparing disease specific deaths between patients with clinically apparent and incidentally discovered ACC are shown in Figure 1. A trend was observed toward increased survival amongst those with ACC discovered incidentally compared to those with clinically apparent ACC, however this failed to reach statistical significance (P=0.08).
DISCUSSION
This manuscript documents an experience with the management of adrenal incidentaloma, identifying adrenocortical carcinoma in 10% of patients who underwent resection of an adrenal incidentaloma. Current guidelines suggest that all patients with adrenal incidentalomas should be investigated with biochemical hormonal screening and contrast enhanced CT (Table III). Biochemical screening should include serum DHEAS, overnight 1 mg dexamethasone suppression testing and 24 hr urinary or plasma catecholamines and metanephrines. Serum aldoster- one/renin ratio should be performed in those with hypertension or hypokalemia. Further confirmatory testing should be ordered if any abnormalities are detected [1,2,11].
Additionally, all patients should also undergo multiphase contrast enhanced CT. Features of a benign adrenal lesion include a homogenous, well circumscribed mass with a diameter less than 4 cm, an unenhanced density of less than 10 Hounsfield units and delayed contrast washout (at 10 or 15 min) of greater than 50% [13]. Where necessary, magnetic resonance imaging (MRI) and positron emission tomography (PET) may give additional information. In those patients with benign appearances on CT and no evidence of adrenal hypersecretion, observation is safe. Our approach to follow-up includes repeat hormonal testing annually with repeat CT initially at 6 months and then annually for 4 years.
The risk of malignancy in adrenal incidentalomas less than 4 cm in diameter is 2% but rises to 25% for lesions larger than 6 cm [4,5,13]. For those lesions with definite benign radiological features at diagnosis, the risk of malignancy is estimated at 1 in 1,000 [14]. Observation for benign lesions is advised as with 5-year follow-up,
| ACC (total 16) | ACC, incidentaloma (7 patients) | Symptomatic ACC (9 patients) | P-Value |
|---|---|---|---|
| Age, years (mean, range) | 43 (25-74) | 46 (17-69) | 0.74 |
| Adrenal size, mm (median, range) | 80 (40-100) | 60 (50-100) | 0.48 |
| Surgical approach | 0.13 | ||
| Laparoscopic | 5 (71%)ª | 2 (22%) | |
| Open | 2 (29%) | 7 (78%) | |
| Median Weiss score median (range) | 3 (3-6) | 5 (3-7) | 0.03 |
| Deaths | 2 (1 unrelated to ACC) | 7 | 0.08 |
ªOne conversion due to high suspicion of malignancy.
Journal of Surgical Oncology
1.0
0.8
Cumulative Survival
0.6
0.4-
0.2
0.0
0
10
20
30
40
50
60
Months
16-47% of patients will develop endocrine abnormalities (subclinical Cushing’s syndrome being most common) and 9-29% of lesions will enlarge by more than 1 cm [7,14]. Surgery should be considered in those with incidentally discovered adrenal masses where the mass is larger than 4 cm in diameter, has a suspicious CT appearance or with significant adrenal hormone hypersecretion. Additionally, patients who during follow-up have an increase in size of the adrenal mass (>1 cm) or who develop biochemical evidence of adrenal hormonal dysfunction should be considered for surgery [1,7,11,12]. In the majority of cases laparoscopic adrenalectomy will be the approach of choice [11,12].
In published surgical series of adrenal incidentalomas, non- functioning adrenocortical adenoma remains the most common diagnosis (36-94%). Other frequent pathological findings include pheochromocytoma, metastases (lung, breast, and melanoma) and benign adrenal masses such as myelolipoma, adrenal cysts, gang- lioneuroma [4-6,11,15]. Of note, in this series there were no metastases in the adrenal incidentaloma group. However for all other histopathological diagnoses, incidence in this surgical series largely parallels results from other similar published series [4-6,11].
Adrenocortical carcinoma is a rare disease with an estimated incidence of 1-2 cases per million of population [11,16]. The most common clinical presentation is of hormonal hypersecretion, with rapidly progressive Cushing’s syndrome being most frequent [16]. Patients with non-functioning tumors may present with local symptoms (abdominal or back pain, nausea) or as an incidental finding. Prognosis is dependent on stage and histopathological grade as determined by Weiss score [17] and until recently was thought to be
TABLE III. Protocol for Investigation and Follow-Up of Adrenal Incidentalomas
Initial investigation of adrenal incidentaloma >1 cm Overnight 1 mg dexamethasone suppression testinga
24 hr urinary catecholamines and metanephrines Serum DHEAS
Serum aldosterone/renin ratio-if hypertensive
Follow-up protocol (for 4 years)
CT adrenal (contrast enhanced)-Initial at 6 months then annually Hormonal testing (as above)-annually
ªMay be substituted with 24 hr urinary free cortisol levels.
almost universally characterized by aggressive behavior and poor prognosis [16,18]. There are however, patients with low grade tumors for whom resection can be curative [3,10,16]. Three recent studies have published data of the genetic profiling of ACC which suggest that there are two distinct clusters of ACC with differing prognoses. Patients with ACC with higher genetic variability have a poorer prognosis and those with less genetic variability have a comparatively better prognosis [19-21]. The relationship between this and clinical features remains uncertain however using the result of this series we hypothesize that this may be related to mode of presentation.
This series investigates only surgically resected adrenal incidenta- loma and hence similar to other surgical series is subject to a high degree of selection bias leading to a high incidence of malignancy amongst adrenal incidentaloma. This manuscript reports the outcome of 16 patients with ACC of which 7 presented as adrenal incidentaloma. As ACC is an extremely rare tumor, the majority of published studies involve small numbers of patients and hence statistical significance of results is difficult to obtain. In this series, those with ACC discovered incidentally had lower grade, non- functioning tumors compared to the increased frequency of higher grade, functional tumors in the symptomatic group. Although it did not reach statistical significance (P=0.08) we did find a trend towards improved survival in those with ACC and an incidental presentation. We propose that ACC may present in two forms, with incidental tumors having an improved prognosis compared to those with clinically apparent ACC. Further studies will be required to clarify this observation.
CONCLUSION
Surgeons should be aware of the differential diagnosis and investigation of adrenal incidentaloma such that appropriate patients are offered resection. Although the risk of ACC is small, those with incidentally discovered ACC who undergo complete resection may have a more favorable prognosis.
ACKNOWLEDGMENTS
Christine J. O’Neill is supported by the New South Wales Cancer Institute.
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