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ORIGINAL ARTICLE - ENDOCRINE TUMORS
Adrenocortical Carcinoma: The Value of Lymphadenectomy
Joshua Tseng, MD1, Timothy DiPeri, MD1, Yufei Chen, MD1, Daniel Shouhed, MD1, Anat Ben-Shlomo, MD2, Miguel Burch, MD1, Edward Phillips, MD1, and Monica Jain, MD1
1Division of Minimally Invasive Surgery and Endocrine Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA; 2Division of Endocrinology, Diabetes and Metabolism, Adrenal Program, Cedars-Sinai Medical Center, Los Angeles, CA
ABSTRACT
Background. Adrenocortical carcinoma (ACC) staging does not account for the number of positive nodes. The prognostic value of quantitative metastatic nodal burden is unknown.
Methods. The National Cancer Database was retrospec- tively queried from 2004-2016 to identify patients with Stage I-III ACC undergoing adrenalectomy. Patients who underwent lymphadenectomy (LAD) were further studied. Demographics, TNM staging, tumor characteristics, and surgical approach were analyzed.
Results. 386 LADs were identified. The median number of nodes examined was 2 (IQR 2-6), with no difference by surgical approach ‘[laparoscopic, 3 (1-3); robotic, 1.5 (1-4.5); open, 2 (1-7), p = 0.493]. In LADs with cNO disease, positive nodes were seen in 17.5% of patients; an average of 6 (1-12) nodes were examined in patients who upstaged to pN1 disease compared with an average of 2 (1-6) nodes in those who remained pNO. Median survival was incrementally worse for patients with more positive nodes (62.8 vs. 21.9 vs. 13.7 vs. 11.3 vs. 10.7 months for 0, 1, 2, 3, and ≥ 4 positive nodes, respectively, p < 0.01). On multivariate analysis, significant prognostic factors for poor survival included older age, ≥ 2 comorbidities, pT3, and pT4. The strongest prognostic factor for poor survival was the number of positive nodes (1 node, hazards ratio [HR] 2.3, 95% confidence interval [CI] 1.5-3.6; 2 nodes, HR 1.3, 95% CI 0.6-3.0; 3 nodes, HR 3.0, 95% CI 1.1-8.0;
≥ 4 nodes, HR 4.0, 95% CI 2.5-6.2). Lymphadenectomy was associated with improved survival (HR 0.82, 95% CI 0.67-0.99).
Conclusions. Higher quantitative metastatic nodal burden is a robust prognostic factor for worse survival in ACC.
Keywords Adrenocortical carcinoma · Lymph node dissection · Survival
Adrenocortical carcinoma (ACC) is a rare and aggres- sive endocrine malignancy with a poor prognosis. It has an incidence of 200 cases per year and carries a 5-year sur- vival rate of 15-44%.1,2 Adrenalectomy with RO resection is the current treatment of choice for patients without evidence of distant metastases.3 3-5
ACC regionally spreads to the ipsilateral renal hilum, peri-renal fat tissue, inter-aortocaval nodes, and bilateral para-aortic nodes.6 Although the existence of nodal metastasis in ACC is known to be associated with worse survival, it is unknown if, as with other cancers, survival worsens with increased metastatic lymph node burden.7,8 Furthermore, due to the rarity of performing lym- phadenectomy in patients with ACC, the survival benefit is unclear.8
The current guidelines for lymphadenectomy are con- flicting, with the National Comprehensive Cancer Network (NCCN) and the European Society of Endocrinology (ENSAT) recommending routine locoregional lym- phadenectomy for suspected or confirmed ACC, whereas the National Cancer Institute (NCI) recommends lym- phadenectomy only if enlarged lymph nodes are present.9 Only ENSAT describes specific regions to target for lym- phadenectomy-the peri-adrenal and renal hilum lymph nodes.1º None of the guidelines address the minimum number of nodes required for an adequate lymphadenectomy.
@ Society of Surgical Oncology 2021
Accepted: 18 October 2021;
Published Online: 18 November 2021
The feasibility of conducting large, prospective studies to answer these questions is limited by the rarity of ACC. Thus, using a national registry of cancer patients, we evaluated the value of concurrent lymphadenectomy as a method of staging and disease control in patients under- going adrenalectomy for nonmetastatic ACC, as well as the prognostic value of quantitative metastatic lymph node burden.
METHODS
The National Cancer Database (NCDB) is a clinical oncology database sponsored by the American College of Surgeons and the American Cancer Society. It captures data from more than 1500 Commission on Cancer (CoC)- accredited facilities and represents more than 70% of newly diagnosed cancer cases nationwide.
The NCDB was retrospectively queried from 2004 to 2016 for all patients with a diagnosis of ACC undergoing adrenalectomy. Patients with evidence of metastatic (cM1) disease were excluded. Data regarding patient age, gender, race/ethnicity, Charlson-Deyo score, insurance status, location, and income quartile were obtained. Treatment facility types were ascertained. Tumor characteristics, including clinical and pathologic T, N, and M stages, tumor size, and laterality, were assessed. Information regarding surgical approach, extent of surgery, regional lymph node sampling, the numbers of lymph nodes examined, and the numbers of lymph nodes positive on pathology were also assessed. Regional lymph node sampling was extracted from the NCDB variable “Scope of Regional LN Surgery,” in which the removal, biopsy, or aspiration of regional lymph node(s) at the time of surgery of the primary site represents a patient who underwent targeted lym- phadenectomy. Based on a prior study by Panjwani et al. that recommended a minimum number of four lymph nodes for accurate staging in ACC, we also assessed the proportion of patients who received an “adequate” lymphadenectomy.11
Patients undergoing lymphadenectomy (LADs) were compared with patients not undergoing lymphadenectomy (non-LADs). The numbers of lymph nodes examined were compared by surgical approach (laparoscopic, robotic, and open). Clinical and pathologic N stages were compared to assess lymphadenectomy as a staging procedure. Patient and tumor characteristics were described as median (in- terquartile ratio) for nonparametric continuous variables, and n (%) for categorical variables. Univariate analysis was performed with the Mann-Whitney U test for nonpara- metric continuous variables and the Kruskal-Wallis test for multiple groups of nonparametric continuous variables. Pearson’s Chi-squared test was used to assess categorical
variables, and Fisher’s exact test was used for categorical variables with small sample sizes. Kaplan-Meier estimate and log-rank test were used to assess median overall sur- vival based on T stage, N stage, whether lymphadenectomy was performed, and the numbers of positive lymph nodes. Multivariable analysis with Cox proportional-hazards regression model was used to assess predictive factors for overall survival. Statistical analyses were performed by using IBM SPSS, Version 25.0 (SPSS, Inc, Armonk, NY).
No preregistration exists for the studies reported in this article. This study was determined to be exempt from Institutional Review Board (IRB) oversight due to the deidentified nature of the data. The data are available upon request from the authors.
RESULTS
A total of 1997 patients with ACC undergoing adrenalectomy were identified, of whom 314 had meta- static (cM1) disease and were excluded. Of the remaining 1683 patients with Stage I-III ACC undergoing adrenalectomy, 386 (22.9%) were LADs and 1297 (77.1%) were non-LADs (Table 1). LADs and non-LADs were similar in terms of age, race, and Charlson-Deyo score. LADs were more like to get their care at an Academic/ Research Program (64.0% vs. 56.5%, p = 0.28) and undergo open surgery (87.5% vs. 58.5%, p < 0.01). LADs also were more likely to have locally advanced tumors (T3 and T4, 54.1% vs. 36.1%, p <0.01) and clinical N1 disease (6.7% vs. 0.4%, p <0.01), and were more likely to be left- sided (62.1% vs. 52.6%, p < 0.01). LADs were more likely to undergo radical resection with removal of other organs (36.3% vs. 11.1%, p < 0.01). There were no statistically significant differences in 30- and 90-day mortality between LADs and non-LADs for each surgical approach (data not included).
The median number of lymph nodes obtained for non- LADs was zero for all operative approaches. The median number of lymph nodes obtained for LADs was 2 (IQR 1-7) and was significantly higher than non-LADs (p <0.01 for all approaches) but was not significantly different between the laparoscopic (3, interquartile range [IQR] 1-3), robotic (1.5, IQR 1-4), and open (2, IQR 1-7) approaches (p = 0.493).
The majority of patients also had pN0 disease (1547 patients, 95.0%). To evaluate the upstaging rate after operation, the pathologic N stages of cN0 and cN1 LADs and non-LADs were compared (Table 2); 17.5% of cN0 LADs had pN1 disease compared with 0.2% of cN0 non- LADs (p < 0.01). This pattern was still present after stratifying for pathologic T stage: in T1/T2 patients, pN1 disease was seen in 12.6% of cN0 LADs, compared to
| Total n = 1683 | Non-LADs n = 1297 (77.1) | LADs n = 386 (22.8) | p value | |
|---|---|---|---|---|
| Age (mean ± SD) | 53.16 ± 15.01 | 53.18 ± 15.16 | 53.12 ± 14.54 | 0.873 |
| Sex | 0.047 | |||
| Male | 668 (39.7) | 498 (38.4) | 170 (44.0) | |
| Female | 1015 (60.3) | 799 (61.6) | 216 (56.0) | |
| Race | 0.581 | |||
| White | 1436 (85.3) | 1111 (85.7) | 325 (84.2) | |
| Black | 153 (9.1) | 112 (8.6) | 41 (10.6) | |
| Asian | 52 (3.1) | 40 (3.1) | 12 (3.1) | |
| Other | 42 (2.5) | 53 (2.5) | 8 (3.1) | |
| Charlson-Deyo score | 0.92 | |||
| 0 | 1268 (75.3) | 976 (75.3) | 292 (75.6) | |
| 1 | 321 (19.1) | 249 (19.2) | 72 (18.7) | |
| 2 | 61 (3.6) | 48 (3.7) | 13 (3.4) | |
| 3 | 33 (2.0) | 24 (1.9) | 9 (2.3) | |
| Facility type | 0.028 | |||
| Community Cancer Program (CCP) | 66 (4.0) | 48 (3.7) | 18 (4.7) | |
| Comprehensive CCP | 440 (26.3) | 355 (27.6) | 85 (22.0) | |
| Academic/Research Program | 972 (58.2) | 725 (56.5) | 247 (64.0) | |
| Integrated Network Cancer Program | 192 (11.5) | 156 (12.1) | 36 (9.3) | |
| Clinical T stage | < 0.01 | |||
| 1 | 147 (9.7) | 137 (11.6) | 10 (2.9) | |
| 2 | 765 (50.2) | 618 (52.3) | 147 (43.0) | |
| 3 | 374 (24.6) | 273 (23.1) | 101 (29.5) | |
| 4 | 237 (15.6) | 153 (13.0) | 84 (24.6) | |
| Clinical N stage | < 0.01 | |||
| 0 | 1652 (98.2) | 1292 (99.6) | 360 (93.3) | |
| 1 | 31 (1.8) | 5 (0.4) | 26 (6.7) | |
| Laterality | < 0.01 | |||
| Right | 752 (45.2) | 606 (47.4) | 146 (37.9) | |
| Left | 912 (54.8) | 673 (52.6) | 239 (62.1) | |
| Surgical approach | < 0.01 | |||
| Laparoscopic | 230 (26.2) | 215 (31.8) | 15 (7.5) | |
| Robotic | 76 (8.7) | 66 (9.7) | 10 (5.0) | |
| Open | 571 (65.1) | 396 (58.5) | 175 (87.5) | |
| Radical resection | 283 (16.8) | 143 (11.1) | 140 (36.3) | < 0.01 |
| No. nodes obtained: median (interquartile range) | 0 | 0 (0-0) | 2 (1-7) | < 0.01 |
| Open | 0 (0-1) | 0 (0-0) | 2 (1-7) | < 0.01 |
| Laparoscopic | 0 (0-0) | 0 (0-0) | 3 (1-3) | < 0.01 |
| Robotic | 0 (0-0) | 0 (0-0) | 1.5 (1-4) | < 0.01 |
| ≥ 1 Node obtained | 377 (23.3) | 8 (0.6) | 369 (98.4) | < 0.01 |
| No. positive nodes | < 0.01 | |||
| 0 | 1547 (95.0) | 1295 (99.8) | 299 (79.5) | |
| 1 | 33 (2.0) | 1 (0.1) | 32 (8.3) | |
| 2 | 13 (0.8) | 0 | 13 (3.4) | |
| 3 | 5 (0.3) | 0 | 5 (1.3) | |
| ≥ 4 | 30 (1.8) | 1 (0.1) | 29 (7.5) |
| PT | pN | Non-LADs | LADs | ||
|---|---|---|---|---|---|
| cN0 | cN1 | cN0 | cN1 | ||
| All | pN0 | 1290 (99.8) | 5 (100) | 297 (82.5) | 5 (19.2) |
| pN1 | 2 (0.2) | 0 | 63 (17.5) | 21 (80.8) | |
| T1/T2 | pN0 | 810 (99.9) | 1 (100) | 146 (87.4) | 1 (50) |
| pN1 | 1 (0.1) | 0 | 21 (12.6) | 1 (50) | |
| T3/T4 | pN0 | 463 (99.8) | 4 (100) | 146 (77.7) | 4 (16.7) |
| pN1 | 1 (0.2) | 0 | 42 (22.3) | 20 (83.3) | |
0.1% of cNO non-LADs (p<0.01); in T3/T4 patients, pN1 disease was seen in 22.3% of cN0 LADs compared with 0.2% of cNO non-LADs (p<0.01). For cN1 LADs, 80.8% of patients had pN1 disease.
An average of 6 (IQR 1-12) lymph nodes were exam- ined in cN0 LADs who upstaged from to pN1 disease compared with an average of 2 (IQR 1-6) lymph nodes for cN0 LADs who had pN0 disease (Table 3). A significantly greater number of patients undergoing “adequate” lym- phadenectomy upstaged from cN0 to pN1 disease (62.7% vs. 39.3%, p < 0.01).
The majority of patients (59.7%) did not undergo adjuvant therapy, whereas 32.8% received either chemotherapy or chemoradiation (Table 4). Rates of adjuvant therapy were higher in pN1 patients (58.1% vs. 39.4%, p < 0.01).
Kaplan-Meier estimates were used to assess survival, and the log-rank test was used to test for statistical sig- nificance. In cN1 patients, the median survival for LADs was similar to non-LADs (21.9 vs. 21.5 months, p = 0.386; Fig. 1a). Patients with pN1 disease had a significantly shorter survival compared with pN0 (14.3 vs. 62.8 months, p < 0.01; Fig. 1b). In patients with pN1 disease, a higher quantitative metastatic lymph node burden was associated with worse survival (62.8 vs. 21.9 vs. 13.7 vs. 11.3 vs. 10.7 months for 0, 1, 2, 3, and ≥ 4 positive nodes, respectively, p < 0.01; Fig. 1c).
| pN0 | pN1 | p value | |
|---|---|---|---|
| Number of nodes examined | 2 (1-6) | 6 (1-12) | < 0.01 |
| 1-3 nodes examined | 173 (60.7) | 22 (37.3) | < 0.01 |
| ≥ 4 nodes examined | 112 (39.3) | 37 (62.7) |
| Total | pN0 | pN1 | p value | |
|---|---|---|---|---|
| None | 1019 (59.7) | 983 (60.6) | 36 (41.9) | <0.01 |
| Radiation | 130 (7.6) | 121 (7.5) | 9 (10.5) | |
| Chemotherapy | 389 (22.8) | 355 (21.9) | 34 (39.5) | |
| Chemoradiation | 170 (10.0) | 163 (10.0) | 7 (8.1) |
In the Cox regression model, independent predictors of mortality include older age (HR 1.02, 95% 1.01-1.02), presence of ≥2 comorbidities by Charlson-Deyo Score (HR 1.54, 95% CI 1.08-2.19), T3 disease (HR 2.08, 95% CI 1.53-2.83), and T4 disease (HR 2.39, 1.73-3.31; Table 5). The strongest prognostic factor for mortality was the number of positive nodes (1 node, HR 2.3, 95% CI 1.5-3.6; 2 nodes, HR 1.3, 95% CI 0.6-3.0; 3 nodes, HR 3.0, 95% CI 1.1-8.0; ≥ 4 nodes, HR 4.0, 95% CI 2.5-6.2). LADs had improved survival (HR 0.82, 95% CI 0.67-0.99).
DISCUSSION
Although lymph node metastases in ACC are associated with significantly worse survival, the role of lym- phadenectomy has not been clearly established in the literature.8 Understanding the benefit of lymphadenectomy is challenging in ACC given that the extent of lym- phadenectomy performed is variable and not well defined.12 The decision to perform a lymphadenectomy is also hindered by the lack of preoperative diagnosis of ACC and/or lymph node metastasis in some cases.13 Finally, the feasibility of large, prospective clinical trials is limited given the rarity of ACC. The goal of our study was to assess the value of lymphadenectomy as both a staging procedure and a method of disease control for non-meta- static ACC.
In our study, only 22.9% of patients with ACC receiving an adrenalectomy underwent targeted regional lym- phadenectomy. This stands in contrast to current NCCN recommendations for concurrent lymphadenectomy when performing an adrenalectomy.14 We found that lym- phadenectomy allowed for improved staging of clinical N0 patients, with 17.5% of cN0 patients upstaging to pN1 disease after lymphadenectomy. This benefit with regard to appropriate staging persisted even after stratifying for pathologic T stage. Thus, our findings indicate that lym- phadenectomy provides additional prognostic information at all T stages, and lymphadenectomy may still be indi- cated in earlier stage disease given that 14.9% of patients with T1 and T2 tumors had lymph node metastases. Accurate lymph node staging is valuable, given that pN1
(a)
(b)
100
(c)
100
pNO
Non-LAD
PN1
100
5555
O nodes
LAD
80
node
2 nodes
80
80
nodes
4 nodes
Survival (%)
Survival (%)
60
Survival (%)
60
60
40
40
40
20
20
20
0
0
0
0
12
24
36
48
60
0
12
24
36
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36
Survival (Months)
Survival (Months)
0
12
48
60
Survival (Months)
| No.at Risk | 0 months | 12 months | 24 months | 36 months | 48 months | 60 months |
|---|---|---|---|---|---|---|
| Non- LAD | 5 | 2 | 1 | 1 | 0 | 0 |
| LAD | 23 | 14 | 8 | 6 | 4 | 2 |
| No.at Risk | 0 months | 12 months | 24 months | 36 months | 48 months | 60 months |
|---|---|---|---|---|---|---|
| Non- LAD | 1490 | 1191 | 927 | 731 | 573 | 450 |
| LAD | 74 | 44 | 23 | 14 | 10 | 5 |
| No. at risk | 0 months | 12 months | 24 months | 36 months | 48 months | 60 months |
|---|---|---|---|---|---|---|
| 0 nodes | 1494 | 1194 | 927 | 731 | 573 | 450 |
| 1 node | 30 | 20 | 11 | 6 | 4 | 1 |
| 2 nodes | 10 | 7 | 5 | 5 | 4 | 3 |
| 3 nodes | 5 | 2 | 1 | 0 | 0 | 0 |
| 4 nodes | 25 | 12 | 2 | 0 | 0 | 0 |
FIG. 1 a Overall survival in cN1 patients, LAD versus non-LAD. b Overall survival by pathologic N stage. c Overall survival by number of positive nodes
| HR | 95% CI | p value | |
|---|---|---|---|
| Age | 1.016 | 1.011-1.022 | < 0.01 |
| Charlson-Deyo score | |||
| 0 | Ref | ||
| 1 | 1.248 | 1.038-1.501 | 0.019 |
| 2 | 1.539 | 1.083-2.186 | 0.016 |
| 3 | 1.523 | 0.973-2.386 | 0.066 |
| Pathologic T stage | |||
| T1 | Ref | ||
| T2 | 1.165 | 0.867-1.566 | 0.309 |
| T3 | 2.080 | 1.527-2.833 | < 0.01 |
| T4 | 2.394 | 1.734-3.305 | < 0.01 |
| Number of Positive Nodes | |||
| 0 | Ref | ||
| 1 | 2.329 | 1.497-3.624 | < 0.01 |
| 2 | 1.319 | 0.580-2.999 | 0.509 |
| 3 | 2.950 | 1.082-8.040 | < 0.01 |
| 4 or more | 3.974 | 2.553-6.186 | < 0.01 |
| Lymphadenectomy | 0.817 | 0.670-0.997 | 0.047 |
disease is associated with significantly worse survival compared with pN0 disease. Documented lymph node metastasis may serve as an indication for adjuvant therapy, such as Mitotane.11
Our study also found that increasing quantitative meta- static lymph node burden was associated with incrementally worse survival for ACC on both univariable and multivariable analysis. This finding was similarly demonstrated by Deschner et al. but was only significant on univariable analysis in their study in contrast to our results.13 The current AJCC 8th edition staging system for ACC only differentiates between N0 and N1 disease based on the presence of any positive lymph nodes.15 Further- more, all T3, T4, and N1 tumors are categorized as Stage 3
disease. We found that quantitative lymph node metastatic burden is the strongest prognostic factor for survival. Our findings suggest that segregation of pathologic lymph node status by the quantitative metastatic lymph node burden may further improve the prognostic value of the AJCC TNM staging system for ACC.
Although lymph node metastasis is associated with worse survival, the role of lymphadenectomy as a proce- dure to improve locoregional control is not well understood. A recent analysis from a multi-institutional database evaluating patients with localized ACC found that a surgeon’s effort to perform a lymphadenectomy-as determined by operative dictation-was associated with improved overall survival.16 Another study from the Ger- man ACC Study Group found that there was a significant reduction in risk of recurrence and disease-related death in those undergoing removal of five or more lymph nodes.1 Despite these findings, a study by Nilubol et al. found no survival benefit in patients with ACC undergoing lym- phadenectomy.18 In our study, lymphadenectomy in cN1 patients was not associated with a survival benefit (21.9 versus 21.5 months, p = 0.386) on univariable analysis. However, after adjusting for age, comorbidities, pathologic T stage, and quantitative metastatic lymph node burden, lymphadenectomy was associated with a modest overall survival benefit of a HR of 0.82. This is preliminary data that lymphadenectomy may increase overall survival in ACC via improved disease control. The caveat to this finding is that the ideal extent of regional lymphadenec- tomy for ACC is still unclear and is beyond the scope of the NCDB database to assess. We are unable to determine the number of nodes removed at each specific lymph node basin during regional lymphadenectomy, which may sig- nificantly influence locoregional control and survival. Additional studies are required to define what an “optimal” lymphadenectomy entails.
In this study, we defined lymphadenectomy based on whether or not the patient underwent targeted regional lymphadenectomy using NCDB variable “Scope of Regional LN Surgery.” For this reason, there is a small number of patients in the non-LAD cohort (n = 8) who had lymph nodes on pathology even though targeted lym- phadenectomy was omitted from their treatment. We kept these patients in the non-LAD cohort to compare outcomes of targeted lymphadenectomy, similar to an intent-to-treat analysis. However, the intent to perform targeted lym- phadenectomy is determined by the NCDB data reviewer, which may introduce bias to our findings.
Our study has some important limitations related to the retrospective nature of a national registry. The NCDB does not contain information about other clinically significant factors that may affect survival outcomes, such as tumor functional status, microscopic pathologic assessment, or molecular characteristics. It also is possible that large, matted nodes may be quantified as a single node on pathology, which would confound the analysis of quanti- tative lymph node burden. The database also lacks information on recurrence rates and disease-free survival, which are important measures for oncologic outcomes. Finally, the small sample size of various elements of this study (e.g., 2 positive nodes, n = 13) may result in type II errors, although the NCDB provides the largest database for rare diseases, such as ACC.
CONCLUSIONS
Increasing quantitative metastatic lymph node burden is associated with incrementally worse survival for ACC. Regional lymphadenectomy during adrenalectomy not only allows for improved staging but also is associated with a survival benefit. Regional lymphadenectomy should be considered as both a staging procedure and a method for improving overall survival.
DISCLOSURES No authors have any commercial interest in the subject of the study.
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