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RESEARCH ARTICLE
WILEY
Adrenal biopsy, as a diagnostic method, is associated with decreased overall survival in patients with T1/T2 adrenocortical carcinoma: A propensity score-matched analysis
Samer A. Naffouje MD1 | Arvind Sabesan MD1 | Julie Hallanger-Johnson MD2
Kedar Kirtane MD3 | Ricardo J. Gonzalez MD4 |
John Mullinax MD4
1Department of Surgical Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
2Endocrine Oncology Program, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
3Head and Neck Oncology Program, H. Lee Moffitt Cancer Center, Tampa, Florida, USA 4Sarcoma Oncology Program, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
Correspondence
Samer A. Naffouje, MD, Department of Surgical Oncology, H. Lee Moffitt Cancer Center, 12902 USF Magnolia Dr, CSB C8111- C009, Tampa, FL 33612, USA. Email: samer.naffouje@moffitt.org
Abstract
Introduction: The standard diagnosis for adrenocortical carcinoma (ACC) is clinical diagnosis (CD) based on radiographic and biochemical studies. Biopsy diagnosis (BD) is seldom required for the suspicion of secondary malignancy. We aim to study the impact of BD in the context of underlying T1/T2 ACC on overall survival (OS) compared with CD.
Methods: National Cancer Database (NCDB) for endocrine malignancies was utilized. Only patients with non-metastatic ACC, whose method of diagnosis and local disease extension were reported, and received a surgical adrenalectomy with curative intent were included. Patients were divided by disease stage into T1/T2, T3, and T4 groups. A propensity score match was applied to those with T1/T2 disease who received CD versus BD and the Kaplan-Meier method was used to compare OS.
Results: In total, 4000 patients with ACC were reported in the database, 1410 met selection criteria. Eight hundred and thirty patients had T1/T2, 365 had T3, and 162 had T4 ACC. Of patients with T1/T2 ACC, 742 (89.4%) received CD versus 88 (11.6%) with BD. A propensity score was calculated per a multivariable regression model with 79 patients matched from each group. Exact matching was applied for margin status and adjuvant therapies. Kaplan-Meier analysis showed a significant difference in median OS between CD versus BD patients in the matched data set (103.89 ± 15.65 vs. 54.93 ±8.22 months; p =0.001). In all comers, patients with T1/T2 ACC and BD had comparable median OS to that of patients with T3 ACC (52.21 ± 9.69 vs. 36.01 ± 3.33 months; p = 0.446).
Conclusion: BD in T1/T2 ACC could be associated with disease upstaging and worse OS outcomes.
KEYWORDS adrenocortical carcinoma, biopsy diagnosis, clinical diagnosis, overall survival
1 INTRODUCTION |
Adrenocortical carcinoma (ACC) is a rare diagnosis with an approxi- mated incidence of one per million population.1,2 Of all adrenal in- cidentalomas found on imaging, the chance of malignancy is as low as 2%-5% for primary, and 0.7%-2.5% for secondary adrenal malig- nancies.3-6 The current standard for the diagnosis of ACC rests heavily on imaging characteristics and functional studies. Radio- graphically, the size of the adrenal tumor and the imaging phenotype can provide an accurate evaluation of whether the incidentaloma is benign or cancerous. Two extensive studies from the National Italian Study Group provided evidence that a cut-off of 4 cm carries high sensitivity and acceptable specificity for the diagnosis of ACC.7,8 Moreover, all ACCs in the Mayo Clinic report measured more than 4 cm in greatest diameter.9 To further improve the diagnostic accu- racy of cross-sectional imaging, adrenal-protocol contrast-enhanced CT scans provide more qualitative details about adrenal masses. Fifteen minutes after administration of intravenous contrast, an ab- solute contrast washout of >60% or a relative contrast washout of >40%, when standardized to the unenhanced phase, approaches 100% accuracy in establishing a diagnosis of benign adenoma versus a malignancy such as ACC or metastases.10,11 Besides, approximately 60% of ACCs are sufficiently secretory to produce clinical symptoms of hormone excess,12-14 with the majority of adult patients mani- festing Cushingoid features or a mixed Cushing and virilization syndrome.2,15
Given the high diagnostic value of radiographic and biochemical workup, 10,11,16-18 the current standard for the diagnosis of ACC does not include adrenal tissue sampling. In addition, cytology provides low yield in ACC diagnosis as it is not easy to distinguish between benign and malignant adrenal tumors. The only definitive diagnostic criterion for malignancy is the presence of metastatic disease or local invasion. Even in the adrenalectomy specimen, the distinction of benign versus malignant adrenal tumors is usually predicted using the Weiss microscopic criteria.19,20 However, needle biopsy often be- comes necessary for the suspicion of extra-adrenal metastatic dis- ease after ruling out the diagnosis of pheochromocytoma.21-24 It is currently unclear whether tumor manipulation during adrenal biopsy with an underlying ACC would cause a significant capsule violation and tumor spillage, a concern of paramount importance during sur- gical adrenalectomy for the same diagnosis. It has been shown that 5-year overall survival (OS) for resected ACCs decreases significantly from T1/T2 tumors (82% and 63% for T1 and T2, respectively) to 50% when tumor infiltration (T3) or invasion (T4) or nodal metastases (N1) are present.25 Tumor spillage and incomplete resection are known poor prognostic factors during surgical resection associated with disease upstaging and shorter survival.26 Some institutional experiences suggested worse outcomes with minimally invasive adrenalectomy, likely due to tumor capsule violation, thus advised to pursue an open resection for ACC.27-31 The current National Comprehensive Cancer Network (NCCN) and European Society of Endocrinology (ESE) generally recommend open resections for ACC size ≥6 cm or local invasion is evident. On the contrary, minimally
invasive adrenalectomy remains reasonable if the tumor is <6 cm, the oncologic principles are respected, and the surgical expertise is available. 32,33
In this study, we aim to analyze the National Cancer Database (NCDB), a large population-based cancer registry that captures ap- proximately 70% of the cancer cases in the United States and study the impact of adrenal biopsy on the survival of patients with T1/T2 ACC.
2 METHODS |
The NCDB for endocrine malignancies 2004-2017 was used for the analysis. Patients with ACC were identified using the International Classification of Diseases in Oncology (ICD-O-3). Patients with metastatic disease were excluded from the analysis. Only patients whose method of diagnosis and local extension of ACC were available were included in the final analysis. Of note, data regarding local tumor extension were extracted from the collaborative staging (CS) reporting system since this variable is not reported in the standard AJCC TNM staging schema. Moreover, patients who received local destruction, no surgical resection, or unknown surgical intervention for their ACC were excluded from the study. Therefore, only patients who received radical surgical resection with curative intent, with or without adjuvant therapies, were selected for the final analysis.
We then divided the selected population based on local disease extension into T1/T2, T3, and T4 groups. Patients with T1/T2 ACC were matched per a propensity score for their diagnostic method of clinical diagnosis (CD) or biopsy diagnosis (BD). The propensity score was calculated for the likelihood of receiving either a CD or BD based on a multivariable logistic regression that includes the following clinical, demographic, and pathologic variables: age, sex, race/ethnicity, Charlson index, side, size, grade, examined nodes, positive nodes, grade, lymphovascular invasion (LVI), surgical approach, margin status, and adjuvant therapies. Patients were matched on a 1:1 ratio using the nearest neighbor method with a caliper width of 0.1 standard deviations. The primary outcome of the study was to compare OS between the T1/T2 CD versus T1/T2 BD groups in the matched data set. The secondary outcome was to compare the OS of patients who had T1/T2 ACC with BD to the T3 and T4 ACC, and study whether the BD method led to upstaging of the disease.
Baseline characteristics were compared between the groups using logistic regression for matched and unmatched cases to assess for adequate balance after matching. Conditional logistic regression was used for comparison of categorical variables and mixed effect modeling for continuous variables. Kaplan-Meier plots were utilized to calculate mean and median survival, and the log-rank test was used to compare survival outcomes. Statistical significance was set at <0.05 throughout the study. IBM SPSS v.25 with R (3.3.3 version) Essentials’ plug-in was used to perform data analysis.
| Age, mean + SD (median) | 55.15 ± 15.43 (56) |
| Sex | |
| Male | 1624 (40.6%) |
| Female | 2376 (59.4%) |
| Race/ethnicity | |
| White | 3177 (79.4%) |
| Black | 382 (9.6%) |
| Hispanic | 266 (6.7%) |
| Other | 175 (4.4%) |
| Charlson score | |
| 0 | 2958 (74.0%) |
| 1 | 745 (18.6%) |
| 2 | 198 (5.0%) |
| 3+ | 99 (2.5%) |
| Side | |
| Right | 1747 (43.7%) |
| Left | 2048 (51.2%) |
| Bilateral | 26 (0.7%) |
| NR | 179 (4.4%) |
| Grade | |
| Well diff. | 107 (2.7%) |
| Moderately diff. | 136 (3.4%) |
| Poorly diff. | 586 (14.6%) |
| NR | 3171 (79.3%) |
| Size | |
| <5 cm | 410 (10.3%) |
| ≥5 cm | 2639 (66.0%) |
| NR | 951 (23.8%) |
| Clinical local invasion | |
| Undetermined (TX) | 672 (16.8%) |
| T1/T2 | 1579 (39.5%) |
| T3 | 638 (16.0%) |
| T4 | 779 (19.5%) |
| NR | 332 (8.3%) |
| Nodes examined | |
| No nodes examined | 3102 (77.6%) |
| Nodes examined | 652 (16.3%) |
| NR | 246 (6.2%) |
| Node status | |
| Negative | 492 (12.3%) |
(Continues)
| Positive | 192 (4.8%) |
| None examined | 3102 (77.6%) |
| NR | 214 (5.4%) |
| Lymphovascular invasion | |
| Negative | 674 (16.9%) |
| Positive | 757 (18.9%) |
| NR | 2569 (64.2%) |
| Metastatic | |
| No | 2077 (51.9%) |
| Yes | 1141 (28.5%) |
| Unknown | 782 (19.4%) |
| Diagnostic method | |
| Clinical | 2603 (65.1%) |
| Biopsy | 1330 (33.3%) |
| NR | 67 (1.6%) |
| Surgery | |
| No surgery | 1124 (28.2%) |
| Ablation/local destruction | 1135 (28.4%) |
| Surgical resection | 1633 (40.8%) |
| Surgery NOS | 108 (2.6%) |
| Margins | |
| Negative | 1927 (48.2%) |
| Positive | 539 (13.5%) |
| NR/NA | 1534 (38.4%) |
| Systemic therapy | |
| No | 3008 (75.2%) |
| Yes | 992 (24.8%) |
| Radiation | |
| No | 3500 (87.5%) |
| Yes | 500 (12.5%) |
| Follow up in months, mean + SD (median) | 35.95 ± 39.24 (20.5) |
Abbreviations: ACC, adrenocortical carcinoma; NCDB, National Cancer Database; NR: not reported.
3 RESULTS |
The NCDB for endocrine malignancies reported 134 998 cases be- tween 2004 and 2017, four thousands of whom had a diagnosis of ACC. The mean age was 53.15 + 15.43 years (median 56 years), and 59.4% were females. The tumors were divided quasi-equally between the right and left laterality (43.7% right, 51.2% left, 5.1% bilateral or not reported). Two-thirds of the tumors (2639, 66%) were 5 cm or larger in diameter, and 45.6% were T1/T2. Table 1 summarizes the demographic, pathological, and treatment characteristics of ACC patients in the NCDB (N = 4000).
After the inclusion/exclusion criteria were applied, we selected 1410 patients with non-metastatic, resected ACC who did not re- ceive neoadjuvant therapy with a reported diagnostic method and known local extension of the adrenal tumor. Figure 1 shows a flow diagram of the study design, including the selection steps and matching. Of the selected 1410 patients, 830 were reported to have T1/T2, 365 patients with T3, and 215 patients with T4 ACC. Of the patients with T1/T2 ACC, 742 (89.4%) received a CD versus 88 (10.6%) who received a BD. Patients with T3 and T4 ACC did not differ in their demographic characteristics from those with T1/T2 ACC but were more likely to have larger tumors, nodal involvement, positive margins, and more often offered adjuvant radiation or systemic therapy. Table 2 demonstrates a comparative analysis of the different stages of ACC in the selected cohort.
To understand the impact of BD on survival, we divided the T1/T2 ACC groups into two subgroups: T1/T2 ACC with CD (N = 742) versus BD (N = 88). We detected some differences in clin- ical and demographic characteristics between the CD and BD groups where the BD patients were slightly older (56.38 + 15.33 vs. 52.94 ± 15.22; p = 0.045), more likely to have nodes in the specimen (21.6% vs. 15.9%; p = 0.039), and had higher rates of pathologic node-positive disease (6.8% vs. 1.9%; p = 0.009). Also, CD patients were more likely to undergo minimally invasive adrenalectomy (20.4% vs. 9.1%; p = 0.018).
We calculated the propensity score to adjust for these differ- ences with a conditional exact match on margin status, receipt of adjuvant systemic therapy, and adjuvant radiation. Table 3 demonstrates a comparison between T1/T2 ACC with CD versus
T1/T2 with BD ACC groups in the unmatched and matched data set. Upon examination of the matched data set, all variables were adequately balanced, as confirmed by standard differences of <0.1 across the table.
Median follow-up for T1/T2 with CD was 58.09 ± 38.98 months versus 50.40 ± 36.81 months in T1/T2 with BD (p =0.108). OS analysis (calculated from the date of diagnosis in both groups) demonstrated a significant difference in median OS for patients with T1/T2 ACC who received CD versus BD (103.89 ± 15.65 vs. 54.93 ± 8.22 months; log-rank p =0.001). Figure 2 shows the Kaplan-Meier curve for OS between T1/T2 CD versus T1/T2 BD in the matched data set. Figure S1 demonstrates the OS analysis between T1/T2 ACC who received CD versus BD in the unmatched data set. In all comers, patients with T1/T2 ACC and BD had com- parable median OS to that of patients with T3 ACC (52.21 ± 9.69 months vs. 36.01 ±3.33 months; log-rank p = 0.446). Figure 3 demonstrates the Kaplan-Meier analysis of OS in the selected database comparing T1/T2 ACC with CD, T1/T2 ACC with BD, T3 ACC, and T4 ACC.
4 DISCUSSION |
In light of the above-mentioned advancements in radiographic techniques and interpretation, and the accuracy of biochemical testing to detect functional adrenal tumors, it becomes evident that adrenal biopsy should have a limited role in the diagnostic workup of ACC, being used only to confirm suspected metastases.
NCDB Endocrine Cancers 2004-2017 N=134,998
Non-adrenal cancers N=130,998
Adrenocortical carcinoma N=4,000
Non-metastatic ACC Known diagnostic method Known local extension N=1,989
Metastatic ACC / Unknown N=1,923 Diagnostic method missing N=32 Local extension missing N=56
Non-metastatic ACC with known local extension, surgically resected without neoadjuvant therapy N=1,410
No surgical resection N=467 Local destruction N=57 Surgery NOS N=43 Neoadjuvant therapy N=12
T1/T2 N=830
T3 N=365
T4 N=215
Clinical diagnosis N=742
Biopsy diagnosis N=88
1:1 matching
Clinical diagnosis N=79
Biopsy diagnosis N=79
| T1/T2 (N= 830) | T3 (N= 365) | T4 (N = 215) | p | |
|---|---|---|---|---|
| Age, mean ± SD | 53.30 ± 15.26 | 54.58 ±14.37 | 52.89 ± 16.02 | 0.316 |
| Sex | ||||
| Male | 324 (39.0%) | 146 (40.0%) | 84 (39.1%) | 0.949 |
| Female | 506 (61.0%) | 219 (60.0%) | 131 (60.9%) | |
| Race/ethnicity | ||||
| White | 675 (81.3%) | 309 (84.7%) | 166 (77.2%) | 0.153 |
| Black | 77 (9.3%) | 22 (6.0%) | 25 (11.6%) | |
| Hispanic | 49 (5.9%) | 19 (5.2%) | 11 (5.1%) | |
| Other | 29 (3.5%) | 15 (4.1%) | 13 (6.0%) | |
| CCI | ||||
| 0 | 604 (72.8%) | 275 (75.3%) | 170 (79.1%) | 0.202 |
| 1 | 174 (21.0%) | 61 (16.7%) | 35 (16.3%) | |
| 2 | 38 (4.6%) | 21 (5.8%) | 5 (2.3%) | |
| 3+ | 14 (1.7%) | 8 (2.2%) | 5 (2.3%) | |
| Side | ||||
| Right | 338 (40.7%) | 157 (43.0%) | 123 (57.2%) | <0.001 |
| Left | 491 (59.2%) | 202 (55.3%) | 90 (41.9%) | |
| NR | 1 (0.1%) | 6 (1.6%) | 2 (0.9%) | |
| Grade | ||||
| Well diff. | 26 (3.1%) | 8 (2.2%) | 9 (4.2%) | 0.011 |
| Moderately diff. | 56 (6.7%) | 11 (3.0%) | 9 (4.2%) | |
| Poorly diff. | 101 (12.2%) | 68 (18.6%) | 32 (14.9%) | |
| NR | 647 (78.0%) | 178 (76.2%) | 165 (76.7%) | |
| Size | ||||
| <5 cm | 128 (15.4%) | 31 (8.5%) | 15 (7.0%) | <0.001 |
| >5 cm | 669 (80.6%) | 330 (90.4%) | 192 (89.3%) | |
| NR | 33 (4.0%) | 4 (1.1%) | 8 (3.7%) | |
| Nodes examined | ||||
| No nodes examined | 660 (79.5%) | 246 (67.4%) | 134 (62.3%) | <0.001 |
| Nodes examined | 137 (16.5%) | 106 (29.0%) | 73 (34.0%) | |
| NR | 33 (4.0%) | 13 (3.6%) | 8 (3.7%) | |
| Node status | ||||
| Negative | 119 (14.3%) | 76 (20.8%) | 53 (24.7%) | <0.001 |
| Positive | 20 (2.4%) | 32 (8.8%) | 22 (10.2%) | |
| None examined | 660 (79.5%) | 246 (67.4%) | 134 (62.3%) | |
| NR | 31 (3.7%) | 11 (3.0%) | 6 (2.8%) | |
| LVI | ||||
| Negative | 205 (45.4%) | 64 (26.4%) | 32 (29.4%) | <0.001 |
| Positive | 140 (31.0%) | 133 (55.0%) | 63 (57.8%) | |
| NR | 107 (23.7%) | 45 (18.6%) | 14 (12.8%) |
(Continues)
| T1/T2 (N= 830) | T3 (N= 365) | T4 (N = 215) | p | |
|---|---|---|---|---|
| Diagnostic method | ||||
| Clinical | 742 (89.4%) | 327 (89.6%) | 171 (79.5%) | <0.001 |
| Biopsy | 88 (10.6%) | 38 (10.4%) | 44 (20.5%) | |
| Margins | ||||
| Negative | 686 (82.7%) | 227 (62.2%) | 110 (51.2%) | <0.001 |
| Positive | 61 (7.3%) | 101 (27.7%) | 81 (37.7%) | |
| NR | 83 (10.0%) | 37 (10.1%) | 24 (11.2%) | |
| Surgical approach | ||||
| Open | 293 (35.3%) | 172 (47.1%) | 96 (44.7%) | <0.001 |
| Minimally invasive | 159 (19.2%) | 70 (19.2%) | 13 (6.0%) | |
| NR | 378 (45.5%) | 123 (33.7%) | 106 (49.3%) | |
| Adjuvant systemic | ||||
| No | 609 (73.4%) | 211 (57.8%) | 141 (65.6%) | <0.001 |
| Yes | 221 (26.6%) | 154 (42.2%) | 74 (34.4%) | |
| Adjuvant radiation | ||||
| No | 729 (87.8%) | 270 (74.0%) | 168 (78.1%) | <0.001 |
| Yes | 101 (12.2%) | 95 (26.0%) | 47 (21.9%) |
Abbreviations: ACC, adrenocortical carcinoma; CCI, Charlson comorbidity index; LVI, lymphovascular invasion; NR, not reported.
To our best knowledge, our study is the first to focus on the potential role of adrenal gland biopsy in upstaging an underlying T1/T2 ACC (T1-T2) with the hypothesis that tumor manipulation could potentially cause capsule violation and tumor spillage or seeding. In our propensity score-matched analysis, we demonstrate that tissue sampling was indeed associated with the worse outcomes of T1/T2 tumors with OS in the BD group being comparable to that of T3 disease. Previous NCDB analyses addressed the question of BD in ACC and its impact on survival. Suman et al.34 reported their survival analysis of ACC patients and concluded that BD does not influence OS. However, that analysis encompassed a different patient population (resected and non-resected ACCs) and followed different standards for adjustments (adjustment was based on tumor size only, not AJCC TNM staging that respect locoregional tumor extension). In our study, we reported patients who received surgical resection as the best therapeutic approach for T1/T2 ACC and adjusted for other confounding factors such as perioperative characteristics and adjuvant therapies in a propensity score match model to compensate for the relatively small sample size.
Another aspect to consider in adrenal biopsies is the potential complications. Williams et al.35 reported their 20-year experience with transcutaneous adrenal biopsies (TAB) in ACCs at the University of Michigan. They concluded that TAB had a sensitivity of 70%, was associated with 11% morbidity, 1.3% mortality (one patient), but did not affect recurrence-free or OS in their cohort. Similarly, this ana- lysis included surgical and nonsurgical ACCs, and no subgroup
analysis was performed for T1/T2 ACCs. In general, the rate of re- ported complications associated with TAB ranged between 0% and 12%,36,37 although difficult to accurately conclude the exact mor- bidity rate given the majority of reports are small institutional series. The most commonly reported complications were hemorrhage, pneumothorax,40,41 pancreatitis,42 adrenal abscess.43 While needle track metastasis appears to be of exceedingly rare occurrence, the other complications, including adrenal bleeding and infections, could arguably be associated with tumor cell seeding and spillage. This occurrence, in turn, could hamper the survival outcomes of patients with T1/T2 disease, but not necessarily patients with already invasive disease (T3-T4).
The shortcomings of our study are mainly attributed to its ret- rospective nature and the inherent weaknesses of national registry analyses, including data loss, misreporting, and most importantly the lack of data on disease-free survival which would be of paramount importance to a study like ours. We also believe that the main indications for resorting to a BD in ACC would be the initial suspicion of a secondary adrenal malignancy or in the context of a nonfunc- tional adrenal tumor with suspicious features. The NCDB is perilously missing the data on secondary cancers and hormonal studies of such tumors, adding another limitation to our work. Herein, we emphasize on the importance of the complete endocrine workup to assess for the autonomous function of an adrenal mass which is imperative before undertaking any intervention such as resection and/or biopsy. While autonomous function alone is not discriminatory for
| Unmatched data set | Matched data set 1:1 | |||||||
|---|---|---|---|---|---|---|---|---|
| T1/T2 ACC clinical | Dx T1/T2 ACC biopsy Dx | SD | p | T1/T2 ACC clinical Dx | T1/T2 ACC biopsy Dx | SD | p | |
| N | 742 | 88 | 79 | 79 | ||||
| Age | 52.94 ±15.22 | 56.38 ±15.33 | 0.101 | 0.045* | 57.49 ± 15.96 | 56.35 ± 14.50 | 0.044 | 0.639 |
| Sex | 0.003 | 0.935 | 0.079 | 0.322 | ||||
| Males | 290 (39.1%) | 34 (38.6%) | 26 (32.9%) | 32 (40.5%) | ||||
| Females | 452 (60.9%) | 54 (61.4%) | 53 (67.1%) | 47 (59.5%) | ||||
| Race/ethnicity | 0.053 | 0.512 | 0.058 | 0.910 | ||||
| White | 604 (81.4%) | 71 (80.7%) | 65 (82.3%) | 64 (81.0%) | ||||
| Black | 70 (9.4%) | 7 (8.0%) | 6 (7.6%) | 6 (7.6%) | ||||
| Hispanic | 41 (5.5%) | 8 (9.1%) | 5 (6.3%) | 7 (8.9%) | ||||
| Other | 27 (3.6%) | 2 (2.3%) | 3 (3.8%) | 2 (2.5%) | ||||
| CCI | 0.050 | 0.550 | 0.083 | 0.776 | ||||
| 0 | 539 (72.6%) | 65 (73.9%) | 60 (75.9%) | 58 (73.4%) | ||||
| 1 | 158 (21.3%) | 16 (18.2%) | 12 (15.2%) | 16 (20.3%) | ||||
| 2 | 34 (4.6%) | 4 (4.5%) | 5 (6.3%) | 3 (3.8%) | ||||
| 3+ | 11 (1.5%) | 3 (3.4%) | 2 (2.5%) | 2 (2.5%) | ||||
| Side | 0.015 | 0.912 | 0.026 | 0.746 | ||||
| Right | 301 (40.6%) | 37 (42.0%) | 31 (39.2%) | 33 (41.8%) | ||||
| Left | 440 (59.3%) | 51 (58.0%) | 48 (60.8%) | 46 (58.2%) | ||||
| NR | 1 (0.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||||
| Grade | 0.079 | 0.159 | 0.018 | 0.975 | ||||
| Well diff. | 26 (3.5%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||||
| Moderately diff. | 51 (6.9%) | 5 (5.7%) | 5 (6.3%) | 5 (6.3%) | ||||
| Poorly diff. | 86 (11.6%) | 15 (17.0%) | 11 (13.6%) | 12 (15.2%) | ||||
| NR | 579 (78.0%) | 68 (77.3%) | 63 (79.7%) | 62 (78.5%) | ||||
| Size | 0.031 | 0.679 | 0.093 | 0.506 | ||||
| ≤5 cm | 117 (15.8%) | 11 (12.5%) | 10 (12.7%) | 11 (13.9%) | ||||
| >5 cm | 595 (80.2%) | 74 (84.1%) | 64 (81.0%) | 66 (83.5%) | ||||
| NR | 30 (4.0%) | 3 (3.4%) | 5 (6.3%) | 2 (2.5%) | ||||
| Margins | 0.057 | 0.257 | 0.000 | 1.000 | ||||
| Negative | 612 (82.5%) | 74 (84.1%) | 68 (86.1%) | 68 (86.1%) | ||||
| Positive | 58 (7.8%) | 3 (3.4%) | 2 (2.5%) | 2 (2.5%) | ||||
| NR | 72 (9.7%) | 11 (12.5%) | 9 (11.4%) | 9 (11.4%) | ||||
| Nodes examined | 0.088 | 0.039* | 0.078 | 0.619 | ||||
| No | 598 (80.6%) | 62 (70.5%) | 58 (73.4%) | 59 (74.7%) | ||||
| Yes | 118 (15.9%) | 19 (21.6%) | 14 (17.7%) | 16 (20.3%) | ||||
| NR | 26 (3.5%) | 7 (8.0%) | 7 (8.9%) | 4 (5.1%) | ||||
| Node status | 0.118 | 0.009* | 0.097 | 0.684 | ||||
| Negative | 105 (14.2%) | 14 (15.9%) | 12 (15.2%) | 12 (15.2%) | ||||
(Continues)
| Unmatched data set | Matched data set 1:1 | |||||||
|---|---|---|---|---|---|---|---|---|
| T1/T2 ACC clinical Dx | T1/T2 ACC biopsy Dx | SD | p | T1/T2 ACC clinical Dx | T1/T2 ACC biopsy Dx | SD | p | |
| Positive | 14 (1.9%) | 6 (6.8%) | 2 (2.5%) | 4 (5.1%) | ||||
| None examined | 598 (80.6%) | 62 (70.5%) | 58 (73.4%) | 59 (74.7%) | ||||
| NR | 25 (3.4%) | 6 (6.8%) | 7 (8.9%) | 4 (5.1%) | ||||
| LVI | 0.066 | 0.377 | 0.083 | 0.590 | ||||
| Absent | 184 (45.5%) | 21 (43.8%) | 13 (35.1%) | 19 (43.2%) | ||||
| Present | 128 (31.7%) | 12 (25.0%) | 13 (35.1%) | 11 (25.0%) | ||||
| NR | 92 (22.8%) | 15 (31.3%) | 11 (29.7%) | 14 (31.8%) | ||||
| Surgical approach | 0.098 | 0.018* | 0.033 | 0.628 | ||||
| Open | 253 (34.1%) | 40 (45.5%) | 28 (35.4%) | 30 (38.0%) | ||||
| MIS | 151 (20.4%) | 8 (9.1%) | 9 (11.4%) | 10 (12.7%) | ||||
| NR | 338 (45.6%) | 40 (45.5%) | 42 (53.2%) | 39 (49.4%) | ||||
| Adjuvant systemic | 198 (26.7%) | 23 (26.1%) | 0.004 | 0.912 | 19 (24.1%) | 19 (24.1%) | 0.000 | 1.000 |
| Adjuvant radiation | 92 (12.4%) | 9 (10.2%) | 0.020 | 0.556 | 6 (7.6%) | 6 (7.6%) | 0.000 | 1.000 |
Abbreviations: ACC, adrenocortical carcinoma; CCI, Charlson comorbidity index; LVI, lymphovascular invasion; MIS, minimally invasive surgery; NR, not reported. * indicate statistically significant.
1.0
0.9
0.8
0.7
Cumulative survival
0.6
0.5
0.4
0.3
0.2
0.1
CD
103.89 ± 15.65 months
p=0.001
0.0
BD
54.93 ± 8.22 months
| 0 | 12 | 24 | 36 | 48 | 60 | 72 | 84 | 96 | 108 | 120 | 132 | 144 | 156 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Clinical diagnosis | Months | |||||||||||||
| N entering | 79 | 70 | 61 | 57 | 47 | 39 | 34 | 24 | 19 | 5 | 3 | 1 | --- | |
| N withdrawing | 2 | 2 | 1 | 4 | 6 | 4 | 5 | 5 | 4 | 2 | 2 | 1 | ||
| N at risk | 77 | 68 | 60 | 53 | 41 | 35 | 29 | 19 | 15 | 3 | 1 | 0 | --- | |
| Cumulative survival | 0.92 | 0.91 | 0.80 | 0.71 | 0.68 | 0.66 | 0.56 | 0.56 | 0.36 | 0.31 | 0.31 | 0.31 | --- | |
| Biopsy diagnosis | ||||||||||||||
| N entering | 79 | 61 | 54 | 48 | 39 | 29 | 22 | 16 | 8 | 4 | 3 | 2 | 1 | |
| N withdrawing | 1 | 0 | 2 | 4 | 3 | 3 | 3 | 3 | 3 | 1 | 1 | 1 | 1 | |
| N at risk | 78 | 61 | 52 | 44 | 36 | 26 | 19 | 13 | 13 | 3 | 2 | 1 | 0 | |
| Cumulative survival | 0.78 | 0.69 | 0.64 | 0.57 | 0.46 | 0.40 | 0.34 | 0.22 | 0.22 | 0.16 | 0.16 | 0.16 | 0.16 | |
malignancy in adrenal masses, the impact on patient outcome in the perioperative period is tremendous. Moreover, ACC is a rare entity; thus, the small sample size was an expected obstacle to the design of this analysis. Finally, a note of high importance for our analysis is the
consideration of immortal bias since the diagnostic methods and the time interval between diagnosis and surgical resection vary between the groups as reported in our results. We believe this is attributed to longer imaging surveillance of T1/T2 with CD before tumor growth
1.0
T1/T2ACC with clinical diagnosis
T1/T2ACC with biopsy diagnosis
0.9
T3 ACC
T4 ACC
0.8
0.7
Cumulative survival
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
36
48
60
72
84
96
108
120
132
144
156
Months
or demonstration of risk features that indicated surgical resection (median interval, 23.50 ± 29.95 months). However, we also believe that referring OS to the time of diagnosis rather than the time of surgical resection, compensates, at least partially, for this inherent bias since the immortal time is included in the survival analysis in the CD group.
We attempted to overcome these deficiencies, to the best of our ability, by excluding missing or questionable data elements and account only for reported variables. We utilized the CS data points to match patients’ staging to the current AJCC v8 staging system to make this analysis more comprehensive and reflective of contemporary standards. We also applied a strict propensity score matching between the study groups to adjust for the many potential confounding factors that could influence survival in our population, namely margin status and adjuvant therapies. Our matched groups demonstrated adequate balance for all the perioperative and demographic variables, suggesting that the difference in OS could truly be attributed to the diagnostic method.
5 CONCLUSION |
We conclude that BD in clinically T1/T2 ACC could be a risk factor associated with unfavorable long-term outcomes since T1/T2 ACC with BD had an OS comparable to that of T3 ACC. Further studies are
warranted to delineate a potential role for adjuvant therapies if disease spread is suspected in T1/T2 ACC with BD.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
AUTHOR CONTRIBUTIONS
Study conception and design: Samer A. Naffouje and Arvind Sabesan. Acquisition of data: Samer A. Naffouje. Analysis and interpretation of data: Samer A. Naffouje, Arvind Sabesan, and John Mulli- nax. Drafting of manuscript: Samer A. Naffouje, Arvind Sabesan, Julie Hallanger-Johnson, Kedar Kirtane, Ricardo J. Gonzalez, and John Mullinax. Critical revision: Samer A. Naffouje, Arvind Sabesan, Julie Hallanger-Johnson, Kedar Kirtane, Ricardo J. Gonzalez, and John Mullinax. All authors have read and approved the manuscript.
DATA AVAILABILITY STATEMENT
The NCDB is a clinical oncology database sourced from hospital registry data that are collected in more than 1,500 Commission on Cancer (CoC)- accredited facilities. Participant user files are released to participating institutions and physicians for research purposes only via a standardized application process and can not be released to third parties.
ORCID
Samer A. Naffouje ID https://orcid.org/0000-0003-4973-9597
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SUPPORTING INFORMATION
Additional Supporting Information may be found online in the sup- porting information tab for this article.
How to cite this article: Naffouje SA, Sabesan A, Hallanger-Johnson J, Kirtane K, Gonzalez RJ, Mullinax J. Adrenal biopsy, as a diagnostic method, is associated with decreased overall survival in patients with T1/T2 adrenocortical carcinoma: a propensity score-matched analysis. J Surg Oncol. 2021;1-11. https://doi.org/10.1002/jso.26639