World Journal of Surgery
Check for updates
ORIGINAL SCIENTIFIC REPORT
Positive Lymph Nodes in Adrenocortical Carcinoma: What Does It Mean?
Alaa Sada1 . Amy E. Glasgow2 . Melanie L. Lyden1 . Geoffrey B. Thompson1 . Benzon M. Dy1 . Travis J. Mckenzie1 . Elizabeth B. Habermann1,2
Accepted: 15 September 2020 @ Société Internationale de Chirurgie 2020
Abstract
Background The role of lymphadenectomy in adrenocortical carcinoma resection is controversial. Therefore, we conducted a population-based study to assess the association between positive lymph nodes (LN) and survival. Methods The Surveillance, Epidemiology, and End Results set of cancer registries were utilized. The associations between positive lymph nodes and tumor size, grade and laterality were assessed. Cancer specific survival (CSS) trends and factors affecting survival were analyzed.
Results A total of 2170 adult patients were identified; 60% underwent resection. Among those resected, LN were examined in 23% and were positive in 25% of patients with LN examined. Patients with positive LN tended to have smaller tumors compared to those with negative LN (12 ± 5 vs 15 ± 11 cm, p = 0.02). The rate of positive LN was higher in right ACC, p = 0.03. Median overall CSS was 21 months, with significant differences between resection (42 months) and no resection (4 months), p < 0.01. Median CSS did not change over time when comparing ACC patients who underwent surgery before 2000, 2000-2009, and 2010-2016. On multivariable analysis including resection group, advanced age, grades III and IV, regional and distant stage, in addition to positive LN were associated with worse survival, p < 0.05.
Conclusion Lymphadenectomy is infrequently performed during ACC resection, and when performed, regional LN involvement tends to be associated with worse survival. Neoplasm size and grade were not associated with LN involvement and therefore, do not inform lymphadenectomy need. Further studies are needed to assess the indications for, and value of lymphadenectomy in ACC.
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy that develops in the adrenal cortex and progresses rapidly to advanced stages [1, 2]. Unfortunately, due to aggressive tumor biology, hormonal over-secretion and advanced
☒ Elizabeth B. Habermann Habermann.elizabeth@mayo.edu
1 Department of Surgery, Mayo Clinic, Rochester, MN, USA
2 Surgical Outcomes Program, Robert D and Patricia E Kern Center for The Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
stages at presentation, these neoplasms are associated with very poor survival-a median overall survival of only 35 months [1]. A recent SEER based study suggested that ACC prognosis not only continues to be poor, but it has been getting worse overtime [3].
Complete surgical resection is the only curative option for ACC as the role of neoadjuvant and adjuvant therapy is very limited [4]. As a result, aggressive surgical resection, even for advanced or metastatic disease, has been advo- cated in carefully selected patients [5, 6]. Moreover, other studies have advocated for regional lymphadenectomy in ACC resection to help improve outcomes [7, 8]. However,
the benefit of routine lymphadenectomy in improving ACC survival is still controversial [2, 9].
The assessment of regional lymphadenectomy in ACC treatment has been limited to case series, as it is not rou- tinely performed, and when it is performed, it is yet to be standardized or defined [2, 9, 10]. Therefore, we used the Surveillance, Epidemiology, and End Results (SEER) set of population-based cancer registries to study the associa- tion between positive lymph nodes and survival in ACC patients, and to assess the relation between positive lymph nodes and tumor size, grade and laterality. Our goal is to better understand the prognostic role of positive lymph node in ACC diagnosis and assess tumor characteristics that can inform the need for lymphadenectomy.
Methods
The Surveillance, Epidemiology, and End Results set of cancer registries (1975-2016) was utilized to identify patients with adrenocortical carcinoma. The SEER pro- gram of the National Cancer Institute (NCI) contains can- cer incidence and survival data from population-based cancer registries covering approximately 34.6% of the U.S. population [11]. This dataset covers information from 18 registries (SEER-18; Alaskan Native, Metropolitan Atlanta, Connecticut, Detroit, Rural Georgia, Greater Georgia, San Francisco-Oakland, San Jose-Monterey, Greater California, Hawaii, Iowa, Kentucky, Los Angeles, Louisiana, New Mexico, New Jersey, Seattle-Puget Sound, Utah) [11].
Adrenocortical carcinoma cases were identified by the International Classification of Diseases for Oncology, Third Edition, ICD-O-3; with a combination of topography code of the adrenal gland NOS (C749) and adrenal cortex (C740) along with histology codes (8370 and 8140).
Patient and neoplasm characteristics were reported by registrars. Information regarding age at death and under- lying cause of death was abstracted from death certificates by the SEER program. The AJCC/TNM stage is not available for ACC patients; therefore, we reported stage by SEER collaborative stage (CS) which categorizes tumors into localized, regional, and distant stages. Localized tumors are confined to the organ of origin without exten- sion beyond the primary organ, and regional stage is determined by direct extension of the tumor beyond the primary site or by spread to regional lymph nodes. If the cancer has spread to parts of the body remote from the primary tumor, it is recorded as distant stage [12]. Lymph node examination and involvement were reported for sur- gically removed nodes identified by the pathologist as opposed to intra-operative examination by the surgeon. If
nodes were “not examined”, they were not identified in the resected specimen [3, 12].
Patients who underwent surgery for exploration only with/without biopsy, underwent bypass surgery only with no resection, had cryosurgery, or who did not undergo surgery, were all included in the no surgical resection group. Patients with unknown surgical status were grouped in the unknown resection group while the rest of patients were grouped under surgical resection group. See “Ap- pendix” section for more details about grouping surgical codes.
Data analysis
Comparison was performed using Kruskal-Wallis for continuous variables and Chi-square tests for categorical variables. Cancer specific survival (CSS) was analyzed using Kaplan-Meier curves and Cox Proportional Hazards regression models. CSS trends were compared to ACC cases diagnosed before 2000, between 2000-2009 and 2010-2016 using the log-rank tests. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).
Results
Overall cohort
A total of 2170 patients were identified over the study period. The average age (SD) was 55.7 (15.3) years, 1240 (57.1%) of patients were females and the majority (85.3%) were white as summarized in Table 1.
Tumor size was reported for 71.0% of cases; among those with reported tumor size, the average size (SD) was 121.4 (93.8) mm. ACC was grade I in 3.1% of cases, grade II in 4.2%, III in 9.2%, IV in 5.3%, while the grade was not available for the rest (78.2%). ACC developed on the left side in 51.4% of cases and on the right in 43.4% while the laterality was unknown in the rest of cases. Tumor stage, as shown in Table 1, was localized for 38.5%, regional for 18.1%, and distant for 35.7%.
Surgical resection was performed for 1307 patients (60.2%); the greatest proportion of these patients had localized or regional disease while only 19.4% had resec- tion for distant metastatic disease as shown in Table 1.
Patients with examined regional lymph nodes
Among patients who underwent surgical resection (N = 1307), lymph nodes were examined in 302 patients (23.1%), and were positive in 76 patients (25.2% of
| No resection (N = 542) | Surgical resection (N = 1307) | Unknown resection (N = 321) | Total (N = 2170) | p value | |
|---|---|---|---|---|---|
| Age | < 0.01ª | ||||
| Mean (SD) | 59.1 (16.1) | 54.3 (14.9) | 55.5 (14.6) | 55.7 (15.3) | |
| Median | 61.0 | 55.0 | 58.0 | 57.0 | |
| Q1, Q3 | 48.0, 70.0 | 44.0, 65.0 | 46.0, 67.0 | 45.0, 67.0 | |
| Range | (19.0-94.0) | (19.0-93.0) | (19.0-97.0) | (19.0-97.0) | |
| Sex | < 0.01b | ||||
| Male | 245 (45.2%) | 525 (40.2%) | 160 (49.8%) | 930 (42.9%) | |
| Female | 297 (54.8%) | 782 (59.8%) | 161 (50.2%) | 1240 (57.1%) | |
| Race | 0.52b | ||||
| White | 456 (84.1%) | 1120 (85.7%) | 274 (85.4%) | 1850 (85.3%) | |
| Black | 50 (9.2%) | 90 (6.9%) | 25 (7.8%) | 165 (7.6%) | |
| Other | 36 (6.6%) | 97 (7.4%) | 22 (6.9%) | 155 (7.1%) | |
| Tumor size (mm) | 0.04ª | ||||
| N | 349 | 1161 | 31 | 1541 | |
| Mean (SD) | 109.7 (64.8) | 124.6 (98.2) | 133.0 (167.3) | 121.4 (93.8) | |
| Median | 100.0 | 110.0 | 100.0 | 105.0 | |
| Q1, Q3 | 71.0, 137.0 | 78.0, 150.0 | 74.0, 165.0 | 75.0, 150.0 | |
| Range | (0.0-820.0) | (1.0-996.0) | (15.0-989.0) | (0.0-996.0) | |
| Tumor size | < 0.01b | ||||
| Missing | 193 (35.6%) | 146 (11.2%) | 290 (90.3%) | 629 (29.0%) | |
| ≤ 5 cm | 41 (7.6%) | 113 (8.6%) | 5 (1.6%) | 159 (7.3%) | |
| 5+ cm | 308 (56.8%) | 1048 (80.2%) | 26 (8.1%) | 1382 (63.7%) | |
| Grade | < 0.01b | ||||
| Grade I | 6 (1.1%) | 47 (3.6%) | 15 (4.7%) | 68 (3.1%) | |
| Grade II | 8 (1.5%) | 69 (5.3%) | 14 (4.4%) | 91 (4.2%) | |
| Grade III | 62 (11.4%) | 113 (8.6%) | 25 (7.8%) | 200 (9.2%) | |
| Grade IV | 17 (3.1%) | 89 (6.8%) | 8 (2.5%) | 114 (5.3%) | |
| Missing | 449 (82.8%) | 989 (75.7%) | 259 (80.7%) | 1697 (78.2%) | |
| Laterality | < 0.01b | ||||
| Right | 237 (43.7%) | 584 (44.7%) | 120 (37.4%) | 941 (43.4%) | |
| Left | 240 (44.3%) | 709 (54.2%) | 167 (52.0%) | 1116 (51.4%) | |
| Unknown | 65 (12.0%) | 14 (1.1%) | 34 (10.6%) | 113 (5.2%) | |
| Stage | < 0.01b | ||||
| Missing | 356 | 766 | 36 | 1158 | |
| In situ | 1 (0.5%) | 0 (0.0%) | 0 (0.0%) | 1 (0.1%) | |
| Localized | 10 (5.4%) | 285 (52.7%) | 95 (33.3%) | 390 (38.5%) | |
| Regional | 15 (8.1%) | 128 (23.7%) | 40 (14.0%) | 183 (18.1%) | |
| Distant | 134 (72.0%) | 105 (19.4%) | 122 (42.8%) | 361 (35.7%) | |
| Unknown | 26 (14.0%) | 23 (4.3%) | 28 (9.8%) | 77 (7.6%) | |
| Nodes positive | < 0.01b | ||||
| Missing | 526 | 1005 | 317 | 1848 | |
| No | 6 (37.5%) | 226 (74.8%) | 3 (75.0%) | 235 (73.0%) | |
| Yes | 10 (62.5%) | 76 (25.2%) | 1 (25.0%) | 87 (27.0%) |
ªKruskal-Wallis
bChi-square
patients whose nodes were examined). The number of examined lymph nodes was reported for 292 patients out of 302 patients who had their lymph nodes examined. The mean (SD) number of examined lymph nodes was 5.5 (7.3) nodes. For those who had positive lymph nodes, 62 out of 76 patients had the number of positive lymph nodes reported with a mean (SD) of 4 (4.6) nodes.
When comparing tumor characteristics among patients who underwent surgical resection and had their regional lymph nodes examined, we found a difference in tumor size and laterality between patients who had positive and negative lymph nodes. Tumor size was smaller in those with positive lymph nodes (11.7 (4.8) cm compared to 15.2 (10.9) cm in patients with negative lymph nodes, p = 0.02). The rate of positive lymph nodes was higher in right ACC (32.5%) compared to the left (20.9%), p = 0.03.There was no difference in tumor grades as shown in Table 2.
Survival and outcomes
Median overall CSS was 21.0 months with significant difference between resection (42.0 months) and no resec- tion (4.0 months) groups, p < 0.01. Median CSS did not change over time when comparing ACC cases that were resected before 2000, between 2000-2009 and 2010-2016 as shown in Fig. 1.
On Cox Proportional Hazard regression including patients who had resection only, advanced age, grades III and IV (Ref: grade I), regional and distant stage (Ref: localized) and positive lymph nodes were associated with worse survival, all p < 0.05. Table 3. There was no dif- ference in survival by sex or tumor size.
On subgroup analysis including patients who had distant metastatic disease only, we found that surgical resection was associated with better survival in this specific group of
patients. The median CSS for patients who had metastatic disease and underwent resection was 10.0 months com- pared to 3.0 months in patients with the same stage who did not undergo resection, p < 0.01 as shown in Fig. 2.
Discussion
Due to the undefined role of regional lymphadenectomy in adrenocortical carcinoma resection, as the majority of studies assessing its prognostic and therapeutic benefits are limited to small case series with controversial results, we conducted a population-based study to assess whether regional lymph nodes involvement in ACC is associated with specific tumor characteristics and worse outcomes. Our results suggest that regional lymphadenectomy is infrequently performed during ACC resection, and when performed, regional lymph nodes involvement tends to be associated with worse survival. We also found that neo- plasm size and grade may not predict regional lymph nodes involvement and therefore, may not identify patients in need of lymphadenectomy.
Adrenocortical carcinoma is an aggressive malignancy with poor survival. For decades, complete surgical resec- tion has been the only curative option as the role of neoadjuvant and adjuvant therapy is modest, at best. Unfortunately, even with complete surgical resection, ACC survival continues to be poor. Our results have shown stable, but poor survival among ACC patients undergoing surgical resection without much progress since 1975. In the absence of other therapeutic options, some have advocated for more aggressive surgical resection as a potential way to improve survival [2, 6]. Recently, there has been increased interest in performing regional lymphadenectomy, which is not performed routinely during ACC resection. Some
| Positive lymph nodes (N = 76) | Negative lymph nodes (N = 222) | p value | |
|---|---|---|---|
| Tumor size | 0.02ª | ||
| Mean (SD) | 11.7 (4.8) | 15.2 (10.9) | |
| Grade | 0.41b | ||
| Grade I | 10 (16.1%) | 1 (4.4%) | |
| Grade II | 10 (16.1%) | 3 (13.0%) | |
| Grade III | 24 (38.7%) | 14 (60.9%) | |
| Grade IV | 18 (29.0%) | 5 (21.8%) | |
| Laterality | 0.03b | ||
| Right | 38 (50.0%) | 79 (35.6%) | |
| Left | 38 (50.0%) | 143 (64.4%) |
ªKruskal-Wallis
bChi-square
Fig. 1 Cancer specific survival trends for patients who had resection
Cancer Specific Survival Over Time Surgical Resection Patients
100
Time Period Events/Total Median (95% CI)
HR (95% CI)
2000-2009
280/471
45.0 (34.0-57.0)
0.92 (0.76-1.13)
90
2010-2016
143/380
53.0 (38.0-NE)
0.86 (0.68-1.08)
<2000
154/245
42.0 (29.0-70.0)
Reference
Logrank P-value: 0.4327
+ Censor
80
Percent Without Event
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
Survival Time (Months)
| Variable | Hazard ratio | 95% CI | p value |
|---|---|---|---|
| Age | 1.01 | 1.01-1.02 | < 0.01 |
| Male | 1.09 | 0.92-1.30 | 0.29 |
| Grade | |||
| I | Reference | ||
| II | 1.29 | 0.64-2.62 | 0.47 |
| III | 2.71 | 1.45-5.01 | < 0.01 |
| IV | 1.99 | 1.05-3.82 | 0.04 |
| Missing | 2.08 | 1.17-3.72 | 0.01 |
| Tumor size | |||
| ≤ 5 cm | Reference | ||
| > 5 cm | 1.12 | 0.79-1.58 | 0.51 |
| Missing | 0.51 | 0.37-0.69 | < 0.01 |
| Stage | |||
| Localized | Reference | ||
| Regional | 2.02 | 1.63-2.50 | < 0.01 |
| Distant | 4.72 | 3.78-5.89 | < 0.01 |
| Unknown | 0.98 | 0.52-1.86 | 0.96 |
| Lymph nodes | |||
| Positive | Reference | ||
| Negative | 0.58 | 0.41-0.82 | < 0.01 |
| Unknown | 0.51 | 0.37-0.69 | < 0.01 |
studies report it is performed in less than 30% of ACC patients with non-metastatic disease, which has led to limited data about its benefits and indications [2, 7-9, 13].
Our study suggests worse survival among resected ACC cases, if there was lymph nodes involvement. This finding, in line with other studies, suggests regional lym- phadenectomy can have prognostic value [14]. However, its therapeutic benefits are still controversial [7, 9]. Some studies have shown that regional lymphadenectomy can improve survival. The German ACC group evaluated 283 ACC patients, of whom 17% underwent regional lym- phadenectomy and found lower recurrence rate and improved disease related survival among patients who had lymphadenectomy [7]. Similarly, the US Adrenocortical Carcinoma Study Group reported their experience with 120 ACC patients, of whom 27% underwent lymphadenec- tomy, and found improves survival in the lymphadenec- tomy group [8]. While the results of these studies are promising, they need to be interpreted cautiously as regional lymphadenectomy is not clearly defined, specifi- cally the technical consideration related to the number of removed lymph nodes and their location [7-9, 13].
Another important clinical question that remains unad- dressed is whether certain tumor characteristics predict regional lymph node involvement. Our study suggests no association between larger tumor sizes, or higher neoplasm grades with lymph nodes involvements. Similarly, another SEER based study reported no association between tumor
Fig. 2 Cancer specific survival for patients who had metastatic disease by surgical resection
Distant Cancer Specific Survival (Five Years) Surgery vs No Surgery
100
Surgery Group
Events/Total Median (95% CI)
HR (95% CI)
No Surgery
308/347
3.0 (3.0-4.0)
2.03 (1.67-2.46)
90
Surgical Resection
169/208
10.0 (8.0-14.0)
Reference
Logrank P-value: <. 0001
+ Censor
80
Percent Without Event
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
Survival Time (Months)
size and lymph nodes metastasis [13]. However, they found association between higher rates of lymph nodes metastasis and higher tumor grades. These conflicting results can be explained by the fact that the majority of ACC patients in the SEER database did not have their neoplasm grades reported as shown in Table 1. Therefore, a more definite conclusion cannot be drawn from the current results. Interestingly, in our study, the rate of positive lymph nodes was significantly higher in right ACC compared to the left. This finding may be explained by the anatomical differ- ences between the right and left adrenal venous drainage.
Our study has limitations inherent to the SEER database. AJCC/TNM staging was not reported for ACC patients; therefore, we were limited to the available staging system utilized by SEER for ACC (localized, regional, distant or unknown). Further, the intent and therapeutic benefit of performing lymphadenectomy, and the location and lymph node basin of the harvested nodes during surgery were unknown, prohibiting us for evaluating potential for stan- dardization of lymphadenectomy for ACC. Lymphovas- cular invasion is not reported in SEER database, which limited our ability to study its association with regional lymph node involvement. In addition, our previous work has shown differences between functional and non-func- tional ACC [1], but as SEER lacks information about tumor functionality, association between functionality and regio- nal lymph nodes involvement could not be performed.
Conclusion
A small proportion of ACC surgical patients had LN examined. Of those who did, positive LN were associated with worse survival. Neoplasm size and grade may not identify patients in need of lymphadenectomy. Right sided ACC tended to have higher rate of positive lymph nodes compared to the left. Further studies are needed to assess the indications, technique, and value of lymphadenectomy during resection of ACC.
Acknowledgements This publication was made possible by CTSA Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.
Author contribution Study conception and design: AS, AG, EH, TM. Acquisition of data: AS, AG. Analysis and interpretation of data: AS, AG, EH, TM, GT, BD, ML. Drafting of manuscript: AS, AG, EH, TM, GT, BD, ML. Critical Revision of manuscript: AS, AG, EH, TM, GT, BD, ML.
Appendix
See Table 4.
| Group | Surgery code |
|---|---|
| No resection | No Surgery of primary Site |
| Incisional, needle, or aspiration biopsy of other than primary site Incisional, needle, or aspiration biopsy of primary site | |
| Exploratory only and incisional, needle, or aspiration biopsy of primary sites or other sites | |
| Bypass surgery, ostomy only and incisional, needle, or aspiration biopsy of primary sites or other sites | |
| Cryosurgery | |
| Resection | Local tumor excision, NOS |
| Simple/partial surgical removal of primary site | |
| Total surgical removal of primary site; enucleation | |
| Radical surgery partial or total removal of the primary site with a resection in continuity with other organs | |
| Partial/simple removal of primary site without dissection of lymph nodes | |
| Partial/simple removal of primary site with dissection of lymph nodes | |
| Radical surgery (partial/total removal of primary site plus partial or total removal of other organs) | |
| Either local tumor excision/polypectomy/excisional biopsy with electrocautery | |
| Either local tumor excision/polypectomy/excisional biopsy with laser ablation | |
| Excisional biopsy | |
| Surgery stated to be "debulking" | |
| Excisional biopsy; polypectomy; excision of lesion | |
| Stated as "debulking" with or without dissection of lymph nodes | |
| Surgery of regional and/or distant site(s)/node(s) | |
| Unknown | Surgery NOS |
| Surgery unknown | |
| Unknown if surgery done |
References
1. Sada A, Asaad M, Bews KA, et al (2020) Comparison between functional and non-functional adrenocortical carcinoma. Surgery 167:216-223
2. Dickson PV, Kim L, Yen TW et al (2018) Evaluation, staging, and surgical management for adrenocortical carcinoma: an update from the SSO Endocrine and Head and Neck Disease Site Working Group. Ann Surg Oncol 25:3460-3468
3. Sharma E, Dahal S, Sharma P et al (2018) The characteristics and trends in adrenocortical carcinoma: a United States population based study. J Clin Med Res 10:636
4. Dickson PV, Kim L, Yen TW et al (2018) Adjuvant and neoadjuvant therapy, treatment for advanced disease, and genetic considerations for adrenocortical carcinoma: an update from the SSO Endocrine and Head and Neck Disease Site Working Group. Ann Surg Oncol 25:3453-3459
5. Laan DV, Thiels CA, Glasgow A et al (2017) Adrenocortical carcinoma with inferior vena cava tumor thrombus. Surgery 161:240-248
6. Dy BM, Strajina V, Cayo AK et al (2015) Surgical resection of synchronously metastatic adrenocortical cancer. Ann Surg Oncol 22:146-151
7. Reibetanz J, Jurowich C, Erdogan I et al (2012) Impact of lym- phadenectomy on the oncologic outcome of patients with adrenocortical carcinoma. Ann Surg 255:363-369
8. Gerry JM, Tran TB, Postlewait LM et al (2016) Lymphadenec- tomy for adrenocortical carcinoma: is there a therapeutic benefit? Ann Surg Oncol 23:708-713
9. Miller BS, Doherty GM (2013) Regional lymphadenectomy for adrenocortical carcinoma. Ann Surg 257:e13-e14
10. Gaujoux S, Brennan MF (2012) Recommendation for standard- ized surgical management of primary adrenocortical carcinoma. Surgery 152:123-132
11. List of the surveillance, epidemiology, and end results (SEER) program registreies. https://seer.cancer.gov/registries/list.html. Accessed on 16 Oct 2019
12. Review of Staging Systems. Available at https://training.seer. cancer.gov/collaborative/intro/systems_review.html. Accessed on 16 Oct 2019
13. Nilubol N, Patel D, Kebebew E (2016) Does lymphadenectomy improve survival in patients with adrenocortical carcinoma? A population-based study. World J Surg 40:697-705
14. Tran TB, Liou D, Menon VG et al (2013) Surgical management of advanced adrenocortical carcinoma: a 21-year population- based analysis. Am Surg 79:1115-1118
Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.