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The prognostic significance of adrenocortical carcinomas identified incidentally
Kara K. Rossfeld MD, MS1 İD Shishir K. Maithel MD2 Jason Prescott MD, PhD3
Tracy S. Wang MD4 Ryan C. Fields MD5 Sharon M. Weber MD6
Jason K. Sicklick MD7 Adam C. Yopp MD8 Quan-Yang Duh MD9
Carmen C. Solorzano MD10 Konstantinos I. Votanopoulos MD11
Ioannis Hatzaras MD, MPH12 Lawrence A. Shirley MD, MS1
George A. Poultsides MD13 and the U.S. Adrenocortical Carcinoma Study Group
1Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio
2Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia
3Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
4Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
5Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
‘Department of General Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 7Department of Surgery, University of California San Diego, San Diego, California 8Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
9Department of Surgery, University of California San Francisco, San Francisco, California
10Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
11Department of Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina
12Department of Surgery, New York University School of Medicine, New York, New York
13Department of Surgery, Stanford University School of Medicine, Stanford, California
Correspondence
Lawrence A. Shirley, Division of Surgical Oncology, Department of Surgery, The Ohio State University, 410W 10th Ave, N908 Doan Hall, Columbus, OH 43210-1267. Email: Lawrence.Shirley@osumc.edu
Background and Objectives: Little is known regarding the difference in prognosis among patients who have an incidentally discovered adrenocortical carcinoma (ACC) vs those who present with signs or symptoms. We aimed to explore differences in the outcomes of these two populations.
Methods: Data were collected on patients who underwent resection of ACC at 1 of 13 institutions between January 1993 and December 2014. Presentations were categorized as incidental vs symptomatic and outcomes were compared.
Results: Among 227 patients, 100 were diagnosed incidentally while 127 patients presented with symptoms/signs. Clinical and pathological features were comparable among incidental vs nonincidental patients with ACC following the exceptions. Patients with incidentalomas were more likely to have a T1/T2 tumor (55.8% vs 34.8%; P < 0.01) and less likely to have a functional tumor (33.7% vs 47.9%; P = 0.04). Patients with an incidental ACC had improved median recurrence-free survival (RFS; 29.4 months) compared with patients with a nonincidental ACC (13.0 months;
P = 0.03); however, on multivariable analysis, incidental ACC was not an independent predictor of survival.
Conclusions: Patients with resected ACC identified incidentally had an improved RFS compared with the patients who presented with symptoms or signs. This difference may be related to the patients with incidental tumors having earlier T-stage disease.
KEYWORDS
carcinoma, functional, hormone, incidentaloma, symptomatic
1 INTRODUCTION
Incidental adrenal masses can represent a diagnostic challenge for practitioners. In addition, the incidence of incidental adrenal masses is increasing because of the improved imaging techniques1 and an aging population.2 Imaging characteristics can help guide management, as tumor size is an indication for resection in the appropriate surgical candidate. When an incidental adrenal mass is identified, adrenocortical carcinoma (ACC) should be considered in the differential diagnoses as this tumor warrants surgical resection. ACC is associated with a poor prognosis as the 5-year overall survival (OS) is only approximately 40%.3-7 Patients with metastatic disease have an even worse prognosis with a median OS of 1 to 2 years.5,7,8 The only potentially curative option for ACC tumors is surgical resection, yet many patients are diagnosed at an advanced stage that precludes a chance for cure.
Although many ACCs are diagnosed incidentally, the prognostic relevance of symptomatic vs asymptomatic presentation has not been well defined. To date, most data on ACC presenting as incidental tumors have come from small case series1 and have failed to demonstrate a statistically significant impact of incidental vs nonincidental presenta- tion on prognosis. Therefore, the objective of the current study was to define the impact of ACCs that presented incidentally relative to patient outcomes. We hypothesized that patients who presented with an “incidentaloma” would have better long-term outcomes compared with patients who presented with symptomatic tumors.
2 METHODS
2.1 Data collection |
Data on patients who underwent a resection for ACC between January 1993 and December 2014 were collected from 13 participat- ing institutions (Emory University, Atlanta, GA; Johns Hopkins Hospital, Baltimore, MD; Medical College of Wisconsin, Milwaukee, WI; New York University, New York, NY; The Ohio State University, Columbus, OH; Stanford University, Palo Alto, CA; University of California at San Francisco, San Francisco, CA; University of Texas Southwestern Medical Center, Dallas, TX; University of Wisconsin, Madison, WI; Vanderbilt University, Nashville, TN; Wake Forest University, Winston-Salem, NC; and Washington University in St. Louis, St. Louis, MO). Patients <18 years of age who underwent resection of pathologically confirmed ACC were excluded (n = 6).
Patients with incomplete data precluding survival analysis were also excluded (n = 16). Data on demographic and clinical characteristics, as well as data regarding presenting complaints, incidental diagnosis, pre- and postoperative laboratory values including hormonal secretion, staging, pathology, adjuvant therapies (including chemotherapy, mitotane, and radiation), recurrence, and mortality were obtained. The Institutional Review Board of each institution reviewed and approved this study.
2.2 Data analysis |
Patients diagnosed with an incidental ACC were compared with the patients who presented with symptomatic disease. Categorical data were compared using the Thermo Fisher exact test. Continuous data were compared using the independent Student t test. Kaplan-Meier curves were used to assess recurrence and OS; data were compared using log-rank tests. Cox regression was utilized to analyze differences in recurrence free and OS among relevant clinical variables. Univariable analysis was performed for the demographic, clinical, and pathologic features, as well as postoperative therapies. Variables with a P value greater than 0.1 on univariable analysis were included in the multivariable analysis. All analysis was performed using IBM SPSS Statistics 22, Armonk, New York.
3 RESULTS
3.1 Case selection
A total of 259 patients underwent resection for ACC between January 1993 and December 2014. Overall, 227 (88.7%) had been classified according to their “incidentaloma” status, with 100 (44.1%) diagnosed with an incidental ACC and 127 (55.9%) diagnosed after presenting with symptoms or signs. A diagram depicting criteria for the selection of the cohort is shown in Figure 1.
3.2 Cohort features
Demographic, clinical, and pathologic features of patients with incidentally identified ACC vs symptomatic ACC are summarized in Table 1. Sex, age at diagnosis, race, American Society of Anesthesiol- ogists class, and body mass index were comparable among patients with an incidental vs a symptomatic tumor. Of note, there were also no
Patients who underwent resection of ACC between January 1993 and December 2014
N=265
Patients with sufficient data to complete survival analysis
N=251
N=227
Patients with incidentaloma status specified
N=100 (Incidentaloma)
N=127 (Non incidentaloma)
differences between the cohorts regarding nodal status, tumor size, tumor weight, surgical margin status, or metastatic disease. Patients with incidentalomas were, however, more likely to have a T1 or T2 tumor (56% vs 35%; P < 0.01). Patients with an incidental ACC were also less likely to have functional tumors compared with the patients who presented with signs or symptoms (34% vs 48%; P = 0.038). There were no differences in the use of adjuvant treatment with mitotane, radiation therapy, or systemic chemotherapy.
3.3 Patient outcomes |
Median recurrence-free survival (RFS) for the entire patient cohort was 16.1 months (95% confidence interval [CI], 10.1-22.1; n = 192). Patients diagnosed incidentally had a longer median RFS (29.4 months) compared with the patients who had a symptomatic ACC (13.0 months; P = 0.03; hazard ratio [HR] 0.66; 95% CI, 0.45- 0.96)(Figure 2). The median OS for the entire cohort was 38.2 months (95% CI, 18.3-58.1; n = 227). OS among patients diagnosed incidentally vs patients presenting with signs/symptoms was 86.3 vs 33.2 months, respectively (P = 0.126; Figure 2).
3.4 Tumor staging
Because patients presenting with incidentalomas were more likely to have lower T stage, RFS, and OS were further evaluated after stratifying for T stage. After stratification, the improved RFS among patients with incidental ACC tumors did not persist (P = 0.228). Median RFS for T1/T2 tumors was 40.4 months among patients with incidental tumors vs 20.9 months for symptomatic patients
| Incidental ACC | Symptomatic ACC | P value | |
|---|---|---|---|
| Sex | |||
| Male | 38% | 40.2% | P = 0.785 |
| Female | 62% | 59.8% | |
| Age | |||
| Mean | 53.8 | 51.5 | P= 0.231 |
| BMI | |||
| Mean | 30.8 | 28.8 | P = 0.149 |
| ASA class | |||
| I/II | 44.3% | 43.2% | P = 1.000 |
| III/IV | 55.7% | 56.8% | |
| Race | |||
| White | 83.3% | 81.5% | P = 0.859 |
| Nonwhite | 16.7% | 18.5% | |
| Mets at presentation | 13.1% | 22.2% | P = 0.085 |
| T stage | |||
| T1/T2 | 55.8% | 34.8% | P = 0.003 |
| T3/T4 | 44.2% | 65.2% | |
| N stage | |||
| N0/NX | 87.5% | 88.7% | P= 0.835 |
| N1 | 12.5% | 11.3% | |
| M stage | |||
| M1 | 12.2% | 22.6% | P = 0.054 |
| Tumor size | |||
| Mean | 11.9 cm | 12.4 cm | P= 0.567 |
| Tumor weight | |||
| Mean | 735 g | 957 g | P= 0.253 |
| Margin status | |||
| R0 | 75.6% | 67.3% | P= 0.216 |
| R1/R2 | 24.4% | 32.7% | |
| Hormonal production | |||
| Functional | 33.7% | 47.9% | P = 0.038 |
| Nonfunctional | 66.3% | 52.1% | |
| Postoperative mitotane | |||
| Percent received | 43.6% | 40% | P = 0.652 |
| Postoperative radiation | |||
| Percent received | 12.2% | 8.7% | P = 0.471 |
| Postoperative chemotherapy | |||
| Percent received | 12% | 19.3% | P = 0.187 |
Abbreviations: ACC, adrenocortical carcinoma; ASA, American Society of Anesthesiologists; BMI, body mass index.
Cohorts were similar except tumor stage and hormonal production.
RFS: Incidental vs. non-incidental ACC
OS: Incidental vs. non-incidental ACC
1.0
1.0
Proportion without Recurrence
0.8-
0.8-
Proportion Surviving
0.6
0.6
0.4-
0.4-
+
0.2
0.2
0.0-
0,0-
0
24
Time (months)
48
72
96
0
24
Time (months)
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(P = 0.334). Among patients with T3/T4 tumors, median RFS was 11.0 months for the incidental cohort vs 10.7 months for the symptomatic cohort (P = 0.431; Figure 3).
3.5 Hormonal secretion |
Patients presenting with incidental tumors were less likely to have functional tumors than patients with signs or symptoms. As such, RFS was stratified for hormonal production (Figure 4). For hormonally inactive tumors, median RFS was 47.9 months for incidental ACCs vs 17.3 months for ACCs presenting with signs and symptoms (P = 0.027). Among patients with hormonally active tumors, patients with incidental ACCs had a median RFS of 8.8 months vs 10.4 months for the cohort with nonincidental ACCs (P = 0.852).
Among patients who initially had an ACC diagnosed incidentally, patients who had tumors that were later noted to be hormonally active on further workup had a shorter RFS compared with the patients who had nonfunctional tumors (8.8 vs 47.9 months; P < 0.01; HR 2.97; 95% CI, 1.57-5.63). OS was also shorter among patients with incidental ACCs that were later noted to be functional (36.5 months) vs patients with incidental ACCs that were nonfunctional (167.8 months; P = 0.02; HR 2.23; 95% CI, 1.11-4.50).
RFS and OS were similar among patients with symptomatic ACCs, regardless of hormonal secretion. Patients with symptomatic non- functional ACCs had a median RFS of 17.3 months vs 10.5 months among patients with symptomatic functional ACCs (P =0.12). Symptomatic nonfunctional ACCs median OS was 37.0 months vs 26.5 months for symptomatic functional ACCs (P = 0.25).
3.6 Univariable and multivariable analysis
Demographic, clinical, and pathologic features, as well as post- operative therapies, were tested independently for differences in RFS and OS. On multivariable analysis, only T stage, M stage, and
hormonal production were predictive of worse RFS (Table 2). For OS, the presence of metastasis at presentation, N stage, and margin status was predictive of worse OS on multivariable analysis (Table 3). Incidentaloma status was not a predictor of either RFS or OS.
4 DISCUSSION
Our study examines the experience of 13 academic medical centers treating patients who underwent resection for ACC. Patients with ACCs identified incidentally had a better RFS compared with patients ACCs that initially presented with signs and symptoms, although the presence of symptoms was not predictive of RFS or OS on multivariable analysis. Patients who had their cancers found incidentally were diagnosed with a lower tumor stage, likely accounting for the difference in RFS.
Patients with incidental ACCs that were later noted to be hormonally active had a shorter RFS than those with nonfunctional incidental ACCs. The finding that functional tumors are associated with worse outcomes is concordant with previous studies on patients with ACC. In a retrospective single-institution study,9 202 consecutive patients diagnosed with ACC were evaluated. Seventy-six percent of patients had functional tumors. Corticoster- oid secretion was associated with a worse OS (HR 3.94) on multivariable analysis. Interestingly, only 70% of patients with functional tumors presented with symptoms of hormonal secretion. In another retrospective single-institution study,10 186 patients who underwent surgery for ACC were evaluated, with 40% having hormonally functional tumors. Higher stage at presentation and secretion of cortisol were both found be independent predictors of worse OS. Other single-institution retrospective studies have shown similar results11,12
Less is known about subclinical hormone secretion in patients with ACC, but as demonstrated in this study, patients presenting with an incidentaloma may have functioning tumors. As pointed out
RFS: Incidentaloma vs. non-incidental ACC T-Stage Group = T1/T2
OS: Incidentaloma vs. non-incidental ACC T-Stage Group = T1/T2
1.0
1.0
0.8
0.8
Proportion without Recurrence
Proportion Surviving
0.6
0.6
0.4-
0.4-
0.2-
0.2
0.0
0.0
6
24
Time (months)
48
72
96
6
24
Time (months)
48
72
96
RFS: Incidentaloma vs. non-incidental ACC T-Stage Group = T3/T4
OS: Incidentaloma vs. non-incidental ACC T-Stage Group = T3/T4
1.0
1.0
Proportion without Recurrence
0.8
0.8
Proportion Surviving
0.6
0.6
0.4
0.4.
0.2
0.2-
0.0
0.0
0
24
Time (months)
48
72
96
6
24
Time (months)
48
72
96
by Grunberg in 1982,13 tumors may be functioning biochemically without clinical evidence of such and may be mischaracterized as a nonfunctional tumor. Hormone secretion may be even more difficult to discern clinically as the population struggles with the obesity epidemic and the metabolic syndrome that accompanies, as the phenotype of Cushing syndrome may be masked by a patients’ habitus or other existing conditions. To add to the diagnostic challenge, there is likely underreporting of virilizing tumors in males and feminizing tumors in females.14 We recommend the routine screening for hormone production for a number of reasons. First, for optimal perioperative care, elevated cortisol may alert clinicians to the possibility of postresection adrenal insufficiency. The hormonal expression can, additionally, demonstrate postoperative adjuvant chemotherapy response.15 Finally, as our study demon- strates, hormonal secretion, even without overt symptoms on presentation, can correlate with worse long-term outcomes.
There are several limitations to this study. The status of a tumor as an incidentaloma depends on practitioners properly designating it as such at the time of diagnosis, and it may be subject to mischaracterization in the setting of retrospective data collection. There is significant heterogeneity in the work-up and management of adrenal tumors, and not all data fields were available for analysis. As only patients with resected ACCs were included, there is a selection bias against patients who were not considered surgical candidates.
In conclusion, patients with incidental ACCs have a better prognosis than patients with ACCs that were symptomatic, which is likely related to a lower tumor stage at the time of diagnosis. Evaluating patients with incidentally identified ACC for hormonal activity is a noninvasive and likely helpful prognostic tool as our findings suggest that patients with functional tumors have a worse prognosis even when hormone production is subclinical.
RFS: Incidentaloma vs. non-incidental ACC: Non-Functional
OS: Incidentaloma vs. non-incidental ACC: Non-Functional
1.0
1.0
0.8-
0.8
Proportion without Recurrence
Proportion Surviving
0.6-
0.6
0.4-
0,4-
02.
0.2
0.0
0,0
6
24
Time (months)
48
72
96
6
24
Time (months)
48
72
96
RFS: Incidentaloma vs. non-incidental ACC: Functional
OS: Incidentaloma vs. non-incidental ACC: Functional
1.0-
1.0-
0.8-
0.8
Proportion without Recurrence
Proportion Surviving
0.6-
0.6-
0.4-
0.4-
4
1
0.2
0.2
0.0
0.0
6
24
48
72
96
0
24
Time (months)
48
72
96
Time (months)
| Variable | P value Univariable | P value Multivariable | HR | CI | |
|---|---|---|---|---|---|
| Lower | Upper | ||||
| Metastasis at presentation | 0.002 | ||||
| T stage | <0.001 | 0.002 | 2.07 | 1.29 | 3.32 |
| N stage | 0.033 | ||||
| M stage | 0.001 | 0.015 | 2.34 | 1.18 | 4.63 |
| Tumor size | 0.009 | ||||
| Hormonal production | <0.001 | 0.048 | 1.57 | 1.00 | 2.46 |
| Postoperative mitotane | 0.001 | ||||
| Incidentaloma | 0.027 | ||||
Abbreviations: CI, confidence interval; HR, hazard ratio.
| Variable | P value | P value | HR | CI | |
|---|---|---|---|---|---|
| Univariable | Multivariable | Lower | Upper | ||
| BMI ≥ 30 | 0.046 | ||||
| Age ≥ 65 | 0.009 | ||||
| ASA class | 0.049 | ||||
| Metastasis at presentation | <0.001 | <0.001 | 7.77 | 3.50 | 17.25 |
| T stage | <0.001 | ||||
| N stage | <0.001 | 0.003 | 4.75 | 1.71 | 13.18 |
| M stage | <0.001 | ||||
| Tumor size ≥ 10 cm | 0.012 | ||||
| Margin status | <0.001 | 0.002 | 3.07 | 1.53 | 6.17 |
| Hormonal production | 0.010 | ||||
| Postoperative mitotane | 0.009 | ||||
| Incidentaloma | 0.126 | ||||
Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index; CI, confidence interval; HR, hazard ratio.
ACKNOWLEDGMENTS
The U.S. Adrenocortical Carcinoma Study Group comprises the listed authors as well as the following.
John E. Phay, MD; Timothy M. Pawlik, MD, MPH, PhD: Division of Surgical Oncology, Department of Surgery, The Ohio State Uni- versity, Columbus, Ohio
Neil Saunders, MD; Lauren M. Postlewait, MD: Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University, Atlanta, Georgia
Jason Glenn, MD: Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
Linda X. Jin, MD: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
Ahmed Salem, MD: Department of General Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Shady Gad, MD: Department of Surgery, University of California San Diego, San Diego, California
John C. Mansour, MD; Natalie Seiser, MD, PhD: Department of Surgery, University of California San Francisco, San Francisco, California
Colleen M. Kiernan, MD, MPH: Division of Surgical Oncology, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
Edward A. Levine, MD: Department of Surgery, Wake Forest School of Medicine, Winston-Salem, North Carolina
Rivfka Shenoy, MD: Department of Surgery, New York University School of Medicine, New York, New York
Thuy B. Tran, MD: Department of Surgery, Stanford University School of Medicine, Stanford, California
ORCID
Kara K. Rossfeld (D http://orcid.org/0000-0002-5240-7385
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How to cite this article: Rossfeld KK, Maithel SK, Prescott J, et al. The prognostic significance of adrenocortical carcinomas identified incidentally. J Surg Oncol. 2018;1-8.