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The American Journal of Surgery
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The American Journal of Surgery”
Preoperative adrenal biopsy does not affect overall survival in adrenocortical carcinoma
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Paritosh Suman ª, *, Natalie Calcatera ”, Chi-Hsiung Wang b, Tricia A. Moo-Young ”, David J. Winchester , Richard A. Prinz C
a Department of Surgery, NorthShore University Health System, Baptist Health Medical Group, Evanston, IL, USA
b Research Institute, NorthShore University Health System, Evanston, IL, USA
” Department of Surgery, NorthShore University Health System, Evanston, IL, USA
ARTICLE INFO
Article history: Received 7 September 2016 Received in revised form 20 January 2017 Accepted 29 January 2017
ABSTRACT
Background: The impact of preoperative biopsy on overall survival (OS) in adrenocortical carcinoma (ACC) is unclear. We analyzed the National Cancer Data Base (NCDB) for factors associated with pre- operative adrenal biopsy and its effect on OS in ACC.
Methods: The NCDB was queried from 2003 to 2012 for M0 ACC. Patients with or without preoperative biopsy were compared for factors associated with an increased rate of biopsy. Survival analysis was performed after adjusting for patient and tumor-related variables.
Results: There were 1782 patients with M0 ACC of whom 332 (19%) had a preoperative biopsy. Treatment outside academic cancer centers (OR 1.36, 95% CI 1.04-1.77, P = 0.023) and male gender (OR 1.45, 95% CI 1.11-1.88, P = 0.006) were associated with an increased rate of biopsy. In patients undergoing adre- nalectomy with negative margins, biopsy failed to impact OS (log-rank P = 0.225, HR 1.20, 95% CI 0.84 -1.72, P = 0.306).
Conclusions: Preoperative adrenal biopsy continues to be performed for ACC with no added survival benefit. Adrenalectomy offers the best chance of survival in patients with ACC.
@ 2017 Elsevier Inc. All rights reserved.
1. Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.72 per million population.1 The incidence of ACC is less than 10% in incidentally discovered adrenal masses.2-5 A pri- mary determinant of the risk of malignancy in an adrenal mass is the size of the lesion. The incidence of ACC is approximately 25% in adrenal tumors greater than 6 cm in size.5,6 Along with a rise in the number of adrenal incidentalomas,5 there has been an increase in the number of patients with ACC. Preoperative confirmation of ACC is usually not pursued and an adrenalectomy is performed either for a functional tumor or for a suspicion of ACC based on the size and imaging characteristics of the lesions. Therefore, the role of preoperative adrenal biopsy in the diagnosis of ACC is very limited. Adrenal biopsies are primarily indicated either to identify meta- static disease from extra-adrenal malignancies or to confirm the
diagnosis of ACC in patients with stage IV disease in order to guide appropriate nonoperative treatment. Adrenal biopsy is associated with infrequent but important complications including violation of the tumor capsule with subsequent needle-track seeding.7-9 However, a substantial number of patients with primary adrenal tumors are still having preoperative biopsies.5,7,10 The literature is limited regarding the effect of adrenal biopsy on the long-term survival of patients with ACC. We studied a large national cancer database to determine the incidence of preoperative biopsy, the factors associated with having it and its effect on long term survival in patients with ACC.
2. Methods
2.1. Patient population
The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. Close to 80% of all newly diag- nosed cancers from approximately 1500 CoC accredited hospitals in the United States are reported in the NCDB. The NCDB provides de-
* Corresponding author. 2650 Ridge Avenue, Walgreen Suite 2507, Evanston, IL 60201, USA
E-mail address: suman.paritosh@gmail.com (P. Suman).
identified and Health Insurance Portability and Accountability Act (HIPAA) compliant data to participating institutions upon request for research purposes. Data were queried for patients with histo- logically proven ACC during the period from 2003 to 2012. The International Classification of Diseases for Oncology, Third Edition, code 8370 was used to identify ACC patients. Only patients with ACC that did not have metastatic disease on initial reporting were included. Adrenalectomy was defined as complete local tumor excision, partial/total surgical removal, enucleation, en bloc exci- sion of surrounding tissue, and debulking. Tumors of all sizes were included. Comparison groups were based on the performance of a preoperative adrenal biopsy. Data about hormone functionality, lympho-vascular invasion (LVI), treatment complications, type of chemotherapy, tumor-recurrence and disease specific survival (DFS) were not available in this database.
2.2. Statistics
Continuous data were described as mean + standard deviation (SD) or median (range). The clinicodemographic data of patients with or without biopsy were analyzed with Student’s t-test or Mann-Whitney U test for continuous variables. Chi-square analysis was used for categorical variables. The time interval between date of cancer diagnosis and death was reported as overall survival (OS). Survival tables were created with Kaplan-Meier (KM) method. Ef- fect of the preoperative biopsy on OS was compared using log-rank test. The impact of clinically relevant variables on OS was calculated with univariate and multivariable Cox proportional hazard models, and was reported as survival hazard ratios (HR) with 95% confi- dence intervals (CI). Univariate and multivariable logistic regression analyses were performed to determine the factors affecting biopsy rates. To accurately determine the effect of biopsy on OS, survival analysis was performed in patients with ACC who underwent adrenalectomy with negative margins, no 30-day perioperative mortality or readmission. A 5% significance level was set for all statistical analyses.
2.3. Bias in preoperative biopsy
There was a possibility of bias in the rate of biopsy based on different preoperative variables. To eliminate these biases and confounding factors, survival analysis was selectively performed in ACC patients undergoing adrenalectomy with negative margins and no immediate 30-day readmission or mortality. Furthermore, a multivariable survival analysis adjusted for demographics, socio- economic status (SES), tumor and treatment related variables was performed on this group to truly discern the impact of preoperative biopsy on OS.
3. Results
There were 1782 patients with ACC who met inclusion criteria. Patient demographic and clinicopathologic variables are described and compared for the biopsy and no biopsy groups in Table 1. Of the 1782 patients, 19% underwent preoperative adrenal biopsy. The frequency of biopsy did not vary with yearly intervals. 76% of pa- tients underwent adrenalectomy. The mean age at diagnosis was 53.3 + 15.3 years (+SD). 23% of patients were older than 65 years of age and the majority of patients were females. A higher percentage (23%) of male patients had a biopsy compared to female patients (16%). Academic centers (16%) had the lowest rate of biopsy compared to community (29%) or comprehensive (21%) cancer centers. Mean tumor size in all patients was 11.8 ± 8.7 cm (±SD). Tumor size did not affect biopsy rates. Income and insurance type also did not affect the rate of biopsy (data not shown).
| Characteristic | All | No Biopsy | Biopsy | P |
|---|---|---|---|---|
| n(%) | n(%) | n(%) | ||
| Total | 1782 | 1450 (81) | 332 (19) | |
| Age (years) | 0.027 | |||
| Mean ± SDª | 53.3 ± 15.3 | 52.6 ± 15.3 | 56.1 ± 15.2 | |
| ≤ 65 | 1379 (77) | 1136 (78) | 243 (22) | |
| > 65 | 403 (23) | 314 (78) | 89 (22) | |
| Gender | <0.001 | |||
| Female | 1064 (60) | 894 (84) | 170 (16) | |
| Male | 718 (40) | 556 (77) | 162 (23) | |
| Comorbidity | 0.054 | |||
| No | 1357 (76) | 1116 (82) | 241 (18) | |
| Yes | 425 (24) | 334 (78) | 91 (22) | |
| Surgery | <0.001 | |||
| No | 383 (21) | 212 (55) | 171 (45) | |
| Yes | 1360 (76) | 1201 (88) | 159 (12) | |
| Tumor size (cm) | ||||
| Mean ± SD | 11.8 ± 8.7 | 11.6 ± 8.6 | 12.6 ± 9.2 | |
| < 6 | 251 (14) | 210 (84) | 41 (16) | 0.565 |
| 6-9.9 | 437 (24) | 358 (82) | 79 (18) | |
| ≥ 10 | 900 (62) | 727 (81) | 173 (19) | |
| Chemotherapy | 0.006 | |||
| Yes | 609 (37) | 477 (78) | 182 (22) | |
| No | 1114 (63) | 929 (83) | 185 (17) | |
| Radiation | 0.161 | |||
| Yes | 232 (13) | 185 (80) | 47 (20) | |
| No | 1528 (81) | 1246 (81) | 282 (19) | |
| Race | 0.870 | |||
| White Non-Hispanic | 1304 (73) | 1063 (82) | 241 (18) | |
| White Hispanic | 105 (6) | 87 (83) | 18 (17) | |
| Black | 159 (9) | 130 (82) | 29 (18) | |
| Others | 214 (12) | 170 (79) | 44 (21) | |
| Cancer center | 0.002 | |||
| Community | 109 (6) | 78 (71) | 31 (29) | |
| Comprehensive | 692 (39) | 550 (79) | 142 (21) | |
| Academic | 978 (55) | 820 (84) | 158 (16) |
a SD, standard deviation.
3.1. Factors associated with preoperative biopsy
On univariate logistic regression analysis (Table 2), the following preoperative factors were associated with an increased likelihood of biopsy: age > 65 years, male gender, and treatment at a comprehensive or community cancer center versus an academic center. Comorbidity, race, SES and tumor size were not associated with biopsy. After adjusting for demographic, SES and tumor fac- tors, male gender (OR 1.45, 95% CI 1.11-1.88, P = 0.006) and treatment at non-academic cancer centers (OR 1.36, 95% CI 1.04-1.77, P = 0.023) were the factors significantly associated with an increased rate of preoperative adrenal biopsy.
3.2. Survival analysis for biopsy in ACC patients
Age > 65 years, presence of comorbidities, tumor size ≥ 10 cm, adjuvant chemotherapy, and radiation treatment were associated with increased hazards of death in univariate survival analysis (data not shown). Biopsy was not significantly associated with OS (HR 1.22, 95% CI 0.88-1.68, P = 0.226). On KM analysis, OS at 5 years and 10 years of follow-up did not differ significantly (log-rank P = 0.225) between biopsy and no biopsy groups in patients un- dergoing adrenalectomy (Table 3, Fig. 1). Additionally, after adjusting for patient, tumor, treatment and SES factors, biopsy still did not have a significant impact on OS (HR 1.20, 95% CI 0.84-1.72, P = 0.306). Survival analysis on patients who did not have adre- nalectomy showed a dismal median OS of 4.04 months. Again, bi- opsy did not have any impact on survival in this group (Table 3).
| Variable | Univariate | Multivariable | ||||
|---|---|---|---|---|---|---|
| ORª | 95% CIb | P | OR | 95% CI | P | |
| Age (years) | ||||||
| ≤ 65 | 1 | 1 | ||||
| > 65 | 1.32 | 1.01-1.74 | 0.043 | 1.29 | 0.94-1.76 | 0.113 |
| Gender | ||||||
| Female | 1 | 1 | ||||
| Male | 1.53 | 1.21-1.95 | <0.001 | 1.45 | 1.11-1.88 | 0.006 |
| Comorbidity | ||||||
| No | 1 | 1 | ||||
| Yes | 1.26 | 0.96-1.65 | 0.092 | 1.17 | 0.87-1.57 | 0.309 |
| Income | ||||||
| High | 1 | 1 | ||||
| Low | 1.14 | 0.88-1.49 | 0.327 | 1.12 | 0.84-1.50 | 0.427 |
| Insurance | ||||||
| Insured | 1 | 1 | ||||
| Uninsured | 0.95 | 0.68-1.33 | 0.777 | 1.09 | 0.74-1.61 | 0.659 |
| Cancer center | ||||||
| Academic | 1 | 1 | ||||
| Non-academic | 1.43 | 1.13-1.82 | 0.003 | 1.36 | 1.04-1.77 | 0.023 |
| Race | ||||||
| White Non-Hispanic | 1 | 1 | ||||
| White Hispanic | 0.91 | 0.54-1.54 | 0.733 | 0.93 | 0.52-1.65 | 0.795 |
| Black | 0.98 | 0.64-1.51 | 0.941 | 1.02 | 0.64-1.64 | 0.932 |
| Others | 1.14 | 1.80-1.64 | 0.471 | 1.20 | 0.82-1.77 | 0.353 |
| Tumor size (cm) | ||||||
| < 6 | 1 | 1 | ||||
| 6-9.9 | 1.13 | 0.75-1.71 | 0.562 | 1.17 | 0.76-1.79 | 0.472 |
| ≥ 10 | 1.22 | 0.84-1.77 | 0.299 | 1.26 | 0.86-1.86 | 0.232 |
a
OR, odds ratio;
b CI, confidence interval.
4. Discussion
Our study shows that preoperative adrenal biopsies are not associated with an improved overall survival, and are mostly per- formed outside academic cancer centers. The patient’s suitability to undergo adrenalectomy seems to be the single most important factor determining long-term survival.
This is the first study from a large national cancer database describing the effect of adrenal biopsy on outcome. The study re- flects a wide practice pattern over the entire United States. Most published studies7,10-14 are limited to single-center experiences which obviously have a limited spectrum of disease presentation and treatment approaches.
Analysis of the unadjusted dataset showed that biopsy does not have any impact on OS in patients undergoing adrenalectomy. This result could be confounded by variables such as demographics, tumor size, and SES factors. Even after eliminating these possible biases by an adjusted multivariable survival analysis, biopsy
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continued to have no association with OS. This correlates well with results of other single-center studies. In a comparison of 36 patients with adrenal biopsy and 248 patients without biopsy, Williams et al. did not find a difference in overall survival (P = 0.07).7 Although not an aim of the present study because of limitations of the database, biopsy has not been shown to have an impact on recurrence and DFS rates in ACC. Biopsy is sometimes performed in poor-surgical risk patients with a large adrenal mass to guide adjuvant treatments. Suspicion for non-adrenocortical carcinoma such as lymphoma can also necessitate biopsy.” 15
The question remains why preoperative biopsies are still being performed in operable ACC? Even though multiple individual fac- tors were found to be associated with adrenal biopsy, on adjusted multivariable analysis, treatment outside an academic medical center was the only modifiable factor associated with an increased rate of preoperative biopsy. One of the possible reasons could be a lack of guideline based treatment protocols and performance of biopsy prior to obtaining appropriate surgical consultation. A large adrenal tumor and the prospect of an extensive operation in a pa- tient with multiple comorbidities may lead to a decision to adopt a non-operative approach which requires a biopsy for tissue diag- nosis. Our data show that preoperative biopsy is associated with a reduced rate of adrenalectomy (48% in the biopsy group vs. 85% in
| Overall survival (KM)ª | Cox survival | ||||||
|---|---|---|---|---|---|---|---|
| Median (range, months) | 5 yr (%) | 10 yr (%) | P | HRb | 95% CIC | P | |
| Surgery | |||||||
| All | 65.5 (1-131) | (52.3) | (36.1) | ||||
| No Biopsy | 67.2 (1-131) | (52.6) | (37.5) | 0.225 | 1 | Multivariable | |
| Biopsy | 62.5 (2-121) | (50.8) | (27.7) | 1.20 | 0.84-1.72 | 0.306 | |
| No Surgery | |||||||
| All | 4.04 (0-145) | (5.2) | (3.3) | 0.359 | |||
| No Biopsy | 3.35 (0-97.8) | (5.9) | 0 | 1 | Multivariable | ||
| Biopsy | 4.80 (0-109) | (6) | (4.5) | 0.92 | 0.70-1.20 | 0.526 | |
a KM, Kaplan-Meier;
b HR, hazard ratio;
” CI, confidence interval.
the no biopsy group, P < 0.001). Patients in the biopsy group were of advanced age and were more likely to be treated at a community cancer center (Table 1). However, there was no difference in comorbidities or tumor size, and none of the patients had meta- static disease. It appears that a preoperative biopsy diagnosis of malignancy tilts further treatment away from surgery. Adrenalec- tomy was associated with a median survival of 65 months compared to 4 months in patients not having an adrenalectomy.
Systemic chemotherapy and radiation treatment did not result in an increased OS in these margin-negative ACC patients. These findings are consistent with the recommendations from other published studies.16,17 Sabolch et al. did not find any effect of ra- diation treatment on overall survival in 58 patients with ACC.16 Adrenalectomy but not chemotherapy was associated with an improved overall survival in a study by Else et al.17 In this study of 391 patients, mitotane therapy increased recurrence free survival but did not improve OS (HR 0.89, 95% CI 0.62-1.27, P = 0.511).
Establishing guideline-based treatment protocols at non- academic institutions could potentially reduce the rates of preop- erative biopsies in patients with ACC. Prior to considering biopsy and chemoradiation in a patient with possible ACC, it should be emphasized that adrenalectomy offers the best chance of survival. A biopsy diagnosis of ACC seems to steer subsequent treatment away from surgery in some patients. Furthermore, biopsy plays no role in the subsequent operative planning for primary ACC and therefore should not be performed beyond the limited set of in- dications where it could alter the treatment plan. Patients with prohibitive perioperative mortality risks, locally advanced ACC, metastatic ACC or metastasis to adrenal glands can benefit from a biopsy.
One major limitation of this study is the lack of complication data related to adrenal biopsy. A complication rate as high as 12% has been reported in the literature.8,9,11,12,18,19 Needle-tract seed- ing7,8 is the most detrimental of these complications and can convert a potentially curable ACC to stage IV. Sensitivity of adrenal biopsy for malignancy has been reported between 70 and 94%. Williams et al. reported a maximum sensitivity of 70%.7 In a multi- institutional study from Europe, Saeger et al. reported an overall sensitivity of 94.6% and specificity of 95.3%.20 Since benign tumors are not included in the NCDB, the sensitivity and specificity of preoperative biopsy for adrenal tumors could not be calculated in present study. Biochemical dysfunction is also a major determinant of symptomatology and survival in ACC. However, the NCDB does not have data on whether tumors are functional or not. This is another limitation of the study.
5. Conclusions
Preoperative adrenal biopsy continues to be performed for ad- renal lesions with no added survival benefit. A guideline based management protocol should be instituted from the time adrenal lesions are detected. This could potentially avoid unnecessary bi- opsies and associated complications. If there is no obvious metas- tasis and no other malignancies that could have spread to the adrenals, resection should be the primary management as this provides the best chance for long-term survival in patients with adrenocortical carcinoma.
Ethical approval
De-identified patient information is freely available to all insti- tutional members who comply with the American College of Sur- geons National Cancer Data Base (NCDB) Data Use Agreement. The Data Use Agreement implements the protections afforded by the Health Insurance Portability and Accountability Act of 1996 and the
ACS-NCDB Hospital Participation Agreement and conforms to the Declaration of Helsinki.
Disclaimer
The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgement
This particular research received no internal or external grant funding.
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