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Informing therapeutic lymphadenectomy: Location of regional metastatic lymph nodes in adrenocortical carcinoma
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Alaa Sada ª, Amy E. Glasgowb,c, Melanie L. Lydenª, Benzon M. Dy ª, Trenton R. Foster ª, Elizabeth B. Habermann b,c, Irina Bancos ”, Travis J. Mckenzie ª,
a Department of Surgery, Mayo Clinic, 200th 1st Street, Rochester, MN, 55905, USA
b Department of Quantitative Health Sciences, USA
” Division of Health Care Delivery Research, Mayo Clinic, Rochester, MN, USA
d Division of Endocrinology, Mayo Clinic, 200th 1st Street, Rochester, MN, 55905, USA
ARTICLE INFO
Keywords: Adrenocortical carcinoma Lymphadenectomy Lymph nodes
ABSTRACT
Background: The anatomic boundaries of lymphadenectomy for adrenocortical carcinoma (ACC) are not defined. Methods: Adults undergoing resection of ACC were included. Locations were categorized based on positive LN locations on final pathology.
Results: Of 231 resected ACC, 6% had positive LN during initial resection. Positive LN in left ACC (n = 7) were: 2 para-aortic, 2 left renal-hilar, 1 para-aortic and left renal-hilar and 1 unknown, while for right ACC (n = 7): 2 para-caval, 1 para-caval and right renal-hilar, 1 inter-aortocaval, 1 celiac, 1 para-aortic, and 1 unknown. Of 55 resections for recurrent ACC, positive LN in left ACC (n = 2) were: 1 para-aortic, and 1 para-aortic with left renal- hilar, while LN for right ACC (n = 7): 2 inter-aortocaval, 2 right renal-hilar, 2 para-caval and one retrocrural. Conclusion: The most common LN metastases are para-caval for right, and para-aortic and left renal-hilar for left ACC. Further studies are necessary to determine the boundaries of lymphadenectomy in ACC resection.
1. Introduction
Adrenocortical carcinoma (ACC) is a devastating malignancy with very limited treatment options other than complete surgical resection.1 Regional lymphadenectomy has been investigated as a treatment option that can improve survival when performed during ACC resection.2,3 However, the benefits of either prophylactic or therapeutic regional lymphadenectomy in improving ACC survival remain controversial as there are conflicting results among studies that evaluated its therapeutic benefits. This is partially due to the fact that regional lymphadenectomy in adrenal surgery is not well defined or standardized.4 There is still paucity of literature describing anatomical boundaries of regional lymphadenectomy in adrenalectomy and the involved lymph node (LN) basins. Therefore, we conducted this study to look at our institutional experience with regard to patients with ACC who underwent planned and unplanned lymphadenectomy with the goal of assessing regional lymph nodes metastases to further elucidate possible patterns of lymph node spread with ACC.
2. Methods
This is a retrospective study of all adult patients who underwent surgical resection of primary or recurrent ACC at any of the Mayo Clinic facilities between 1/1/1997 and 12/30/2017. Medical charts, operative and pathological reports were reviewed to determine locations of removed and involved regional lymph nodes and to assess if regional lymphadenectomy was planned or unplanned (ie: when lymph nodes were found incidentally within the specimen but the surgeon did not intend to performed lymphadenectomy). Preoperative radiology images were reviewed to determine if lymphadenopathy was suspected on preoperative images. LN locations were categorized as inter-aortocaval, para-caval, para-aortic, right renal-hilar, left renal-hilar, retro-crural and/or celiac, based on locations of LN identified as positive on final pathology reports. 30-day complications were reported based on Clavien Dindo classification. Variables were analyzed using Chi-square, Fisher’s Exact and Wilcoxon Rank Sum tests. Statistical analysis was performed using SAS version 9.4 statistical software (SAS Institute, Inc. Cary, NC).
* Corresponding author. Department of Surgery, Mayo Clinic, 200 1st ST SW, Rochester, MN, 55905, USA.
E-mail address: Mckenzie.Travis@mayo.edu (T.J. Mckenzie).
https://doi.org/10.1016/j.amjsurg.2021.10.014
3. Results
A total of 231 patients underwent resection for ACC over the study period; of those 55 (23.8%) underwent secondary resection for recurrent ACC. The median (IQR) number of CT scans performed after surgery per patient (for any indication) was 5 (2,8). The median (IQR) duration of follow-up was 24 (13, 73) months.
During resection of primary ACC (n = 231), regional lymph nodes were removed in 51 patients (22.0%) and were positive in 14 (6%) patients. Out of 51 patients with resected regional LN, 33 patients had left ACC. Locations of removed LN during initial resection in patients with left ACC (n = 33 patients) were: 12 para-aortic, 3 left renal-hilar, 3 para-aortic and left renal-hilar, 1 para-aortic and para-caval, 1 para- aortic and para-caval and left renal-hilar, 1 para-aortic and peri- choledochal, 1 para-aortic with peri-choledochal and hepatoduodenal, and 11 regional but un-specified locations. Positive LN locations during initial resection in left ACC (n = 7 patients) were: 2 patients with para- aortic LN, 2 left renal-hilar, 1 para-aortic and left renal-hilar and 2 un- known. Table 2 shows total number of removed and positive LN during initial ACC resection.
Out of 51 patients with resected LN, 18 had right ACC. Locations of removed LN in right ACC were (n = 18 patients): 5 para-caval, 2 inter- aortocaval, 1 para-aortic, 1 para-aortic and paracaval, 1 patient had LN removed from all previous mentioned location in addition to right renal- hilar (para-caval, inter-aortocaval, para-aortic, right renal-hilar), 1 ce- liac, and 7 had regional unspecified location. Location of positive LN for right ACC (n = 7): 2 para-caval, 1 para-caval and right renal-hilar, 1 inter-aortocaval, 1 celiac, 1 para-aortic, and 1 unknown. Preoperative CT suggested lymphadenopathy in 6 positive LN cases, did not suggest lymphadenopathy in 2, and was not available for 6 patients. The median (IQR) examined number of LN was 3 (1,7), and of metastatic LN was 1 (1,3). There was no difference in median primary tumor size, histolog- ical grade, laterality, or rate of lymphovascular invasion among patients with negative and positive LN, P > 0.05 as shown in Table 1. Planned lymphadenectomy was performed in 31 patients (10 had positive LN), unintended lymphadenectomy when regional LN was discovered inci- dentally in the specimen occurred in 4 patients (0 had positive LN); it is unknown whether the rest (n = 16) had planned or unplanned lym- phadenectomy. Table 2 shows total number of removed and positive LN per intent of lymphadenectomy. The median (IQR) examined number of LN among patients who underwent planned lymphadenectomy (total 31 patients) was 3.5 (1,9).
30-day follow-up was completed in 125 patients; 54% of those who underwent surgery. Among patients with 30-day follow-up, the rate of
| Positive LN (N = 14) | Negative LN (N = 37) | P- value | |
|---|---|---|---|
| Tumor size (cm) | 0.12ª | ||
| # of known tumor size | 11 | 36 | |
| Median (IQR) | 11.5 (10.0,12.4) | 15.0 (11.0,20.0) | |
| Tumor grade | 1.00b | ||
| # of known tumor grade | 5 | 14 | |
| High grade, n (%) | 4 (80%) | 11 (78.6%) | |
| Low grade, n (%) | 1 (20%) | 3 (21.4%) | |
| Laterality, n (%) | 0.20b | ||
| Right | 7 (50%) | 11 (29.7%) | |
| Left | 7 (50%) | 26 (70.3%) | |
| Lymphovascular invasion, n | 0.67b | ||
| (%) | |||
| Absent | 4 (33.3%) | 14 (38.9%) | |
| Present | 5 (41.7%) | 17 (47.2%) | |
| Unknown | 3 (25.0%) | 5 (13.9) |
a Wilcoxon rank sum test.
b Fisher’s exact test.
| Type of lymphadenectomy, nª | Location of removed LN, (nª) | Location of positive LN, (na) |
|---|---|---|
| Planned lymphadenectomy, left ACC (n = 19) | Para-aortic (9) L ** renal hilar (2) Para-aortic + L renal hilar (3) | Para-aortic (1) L ** renal hilar (1) - Para-aortic only (1) - Para-aortic + L renal hilar (1) |
| Para-aortic + para-caval (1) | Para-aortic + para- caval (0) | |
| Para-aortic + L hilar + para-caval (1) | Para-aortic + L hilar + para-caval (0) | |
| Para-aortic + peri- choledochal (1) | Para-aortic + peri- choledochal (0) Para-aortic + peri- choledochal + hepatoduodenal (0) Regional, unspecified (1) | |
| Para-aortic + peri- choledochal + | ||
| hepatoduodenal (1) Regional, unspecified (1) | ||
| Planned | Para-caval (4) | Para-caval (1) Para-aortic (0) Inter-aortocaval (1) Para-aortic only (1) |
| lymphadenectomy, right ACC (n = 12) | Para-aortic (1) Inter-aortocaval (2) Para-aortic + para-caval (1) | |
| R *** renal hilar + para- caval + para-aortic + Inter-aortocaval(1) | Para-caval + R renal hilar (1) | |
| Celiac (1) | Celiac (1) | |
| Regional, unspecified (2) | Regional, unspecified (0) | |
| Unintended | Para-aortic (2) | Para-aortic (0) |
| lymphadenectomy, left ACC (n = 4) | Regional, unspecified (2) | Regional, unspecified (0) |
| Unknown if | L ** renal hilar (1) | L ** renal hilar (1) |
| lymphadenotomy was planned, left ACC (n = 10) | Para-aortic (1) Regional, unspecified (8) | Para-aortic (0) Regional, unspecified (1) |
| Unknown if | Para-caval (1) | Para-caval (1) |
| lymphadenotomy was planned, right ACC (n = 6) | Regional, unspecified (5) | Regional, unspecified (1) |
a
ª n = reflect number of patients, L ** = left, R *** = right.
30-day complications was 48.1% in patients who underwent regional lymphadenectomy vs 35.7% in those who did not, p = 0.27. Among patients who developed complications in the regional lymphadenec- tomy group, 61.5% had Clavien Dindo class I/II complications and 38.5% had class III/IV, while in patients who developed complications but did not undergo regional lymphadenectomy, 85.7% had class I/II and 14.3% had class III/IV, p = 0.06. Most complications in the lym- phadenectomy group were due to the magnitude of multi-visceral resection rather than the lymphadenectomy itself except for one pa- tient who developed chylous ascites that was managed with dietary changes and paracentesis.
Neoadjuvant chemotherapy was administered to 3 patients out of 231 who underwent surgery; 1 patient had regional lymphadenotomy and two did not (1 of those patients who did not have regional lym- phadenotomy, received both neoadjuvant and adjuvant chemotherapy). Among patients who had regional lymphadenotomy: 35.9% received adjuvant multi-agent chemotherapy, 41% received adjuvant mitotane only, 20.5% were recommended to receive chemotherapy but unknown if was given, while the rest did not receive adjuvant chemotherapy. On the other hand, among patients who did not have regional lymphade- notomy: 43.4% received adjuvant multi-agent chemotherapy, 44.9% received mitotane only, 8.5% were recommended to receive adjuvant chemotherapy but unknown if was given, and the rest did not receive adjuvant chemotherapy, p = 0.23. Adjuvant radiation therapy was given
to 20% of patients who did not have regional LN removed vs 12.2% in patients who had regional LN examined, p = 0.29.
Of 55 resections for recurrent ACC, 9 patients had regional lym- phadenectomy; two of them had lymphadenectomy during initial resection. Positive LN locations for recurrent left ACC (n = 2) were: 1 para-aortic, and 1 para-aortic with left renal-hilar, while LN locations for recurrent right ACC (n = 7) were: 2 inter-aortocaval, 2 right renal-hilar, 2 para-caval and one retrocrural.
4. Discussion
Regional lymphadenectomy in adrenocortical carcinoma resection is not standardized as the anatomical boundaries and the involved regional lymph node basins are not well described. To our knowledge, this is the first study that looked at the location of regional lymph node metastases in primary and recurrent adrenocortical carcinoma. Our results suggest that the most common sites for right ACC regional LN metastases are para-caval lymph nodes and for left ACC regional LN metastases are para-aortic and left renal hilar lymph nodes.
Formal regional lymphadenectomy is not routinely performed dur- ing ACC resection. Based on our study using the SEER population based cancer registries, regional lymphadenectomy was performed in 23% of all ACC patients undergoing resection.4 The low rate of regional lym- phadenectomy for ACC may be because its therapeutic and prognostic benefits have been debatable.5 This is due to the fact that unlike regional lymphadenectomy performed for other types of malignancy, there is neither anatomical definition of adequate regional lymphadenectomy for ACC nor a good numeric definition of adequate number of regional lymph nodes that need to be retrieved.2,5,6 The German ACC group defined regional lymphadenectomy if 5 or more lymph nodes were removed.º Our previous SEER study showed that the mean (SD) number of examined lymph nodes in ACC was 5.5 (7.3) nodes while in the current study, we found that median number of examined lymph nodes was 3.4 While these findings can provide some insight about the average number of retrieved lymph nodes during ACC lymphadenectomy, a clear anatomical definition may be of a better value.
Our current study showed that the most common locations for lymph node metastases in left ACC are para-aortic and left renal hilar, and the most common locations for right ACC are para-caval LN. These results are in line with another study performed by the German ACC group that included ACC patients with lymph node metastases after initial curative resection and found that in left ACC, LN recurrence was detected in left renal hilum (50%), in the perirenal fat tissue cranial to the renal hilum (ventral, 47%; dorsal, 55%), para-aortic (47%), inter-aortocaval (22%), and/or in the perirenal fat tissue caudal to the renal hilum (ventral, 20%; dorsal, 17%); while for right ACC, LN metastases were found in perirenal fat tissue cranial to the renal hilum (dorsal, 55%; ventral, 45%), interaorto-caval (35%), in the area of the right renal artery (10%), and/or paracaval (15%).7 While these results support our findings, it is important to note that our study included both primary and recurrent ACC while the previous study focused on recurrent ACC only.7 The European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal tumors (ENSAT) suggested that routine locoregional lymphadenectomy for ACC should include as minimum the periadrenal and renal hilum nodes besides and any suspicious or enlarged LN.8 Moreover, they also suggested that celiac axis, superior mesenteric artery, para-aortic node and/or paracaval lymphadenectomy ipsilateral to ACC need to be considered.8 A clinical review of the literature describing the lymphatic anatomy of the adrenal glands also suggested that common locations for LN metastases in ACC are celiac, renal hilar, para-aortic and para-caval LN while positive LN at the origin of the celiac trunk and the superior mesenteric artery are noted in more advanced disease.9
Preoperative CT images suggested lymphadenopathy in 6 patients in our cohort who were found to have positive LN on final pathology and did not show lymphadenopathy in 2 patients with positive LN. Addi- tionally, about third of patients in whom regional lymphadenectomy was intended, were found to have positive lymph nodes on final pa- thology. These findings highlight the importance of considering regional lymphadenectomy in ACC resection when pre-operative and intra- operative evaluations are suspicious for LN involvement.
The main aim of our study was to assess the anatomical locations of regional lymph node metastasis in ACC. While some studies suggest that locoregional lymphadenectomy improves survival, the benefits of lym- phadenectomy are still questionable, and our study cannot address this topic. Given, the relatively small cohort size, we were underpowered to study any survival difference between patients who underwent regional lymphadenectomy versus those who did not.
Although the rate and severity of 30-day complications did not reach statistical significance between groups, the rate was higher in patients who underwent regional lymphadenectomy. Further studies are criti- cally needed to assess the short-term complications and long-term sur- vival of regional lymphadenectomy.
Our study has limitations related to the retrospective design and small cohort of patients. Preoperative images and intra-operative eval- uations may have guided the operative surgeons to perform or not perform lymph node removal from specific locations and our study may have missed other lymph node locations that were not examined. As ACC is a rare tumor, we had to include patients over a relatively long duration of time. The imaging technology improved over the study duration and lymph nodes metastasis may have been missed on pre- operative images performed in the earlier portion of the study. While our study provided insight about locations of LN metastases in ACC, metastases to other locations need to be investigated. Additionally, in contrast to our previous SEER study that suggested that LN metastases are more common in right ACC, this study was underpowered to detect a difference in the rate of positive LN between right and left tumors.4
5. Conclusion
The most common sites for LN metastases are para-caval for right ACC, and para-aortic and left renal-hilar for left ACC. However, more distant sites may be involved, including inter-aortocaval, celiac, and retrocrural. Further studies are necessary to determine the utility and the boundaries of therapeutic lymphadenectomy during resection of ACC.
Disclosure
The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. No outside funding for research was obtained for this project.
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