ELSEVIER
Surgery
journal homepage: www.elsevier.com/locate/surg
SURGERY NOWEMBER 2018
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Which lymphadenectomy for adrenocortical carcinoma?
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Charles de Ponthaud, MDa,b,c, Soumaya Bekada, MDb,c, Camille Buffet, MD, PhDa,d, Malanie Roy, MDa,d, Anne Bachelot, MD, PhDa,e, Amine Ayed, MDF, Fabrice Menegaux, MD, PhDa,b, Sébastien Gaujoux, MD, PhDa,b,c,*
a Sorbonne University, Paris, France
b Department of General, Visceral, and Endocrine Surgery, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
” Department of Hepato-biliary and Pancreatic Surgery and Liver Transplantation, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
d Department of Endocrinology, AP-HP, Hospital Pitié Salpétrière, Paris, France
e Department of Endocrinology and Reproductive Medicine and Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Centre de Référence des Pathologies Gynécologiques Rares, AP-HP, IE3M, Hôpital Pitié-Salpêtrière, Paris, France Radiology Department, Hôpital Pitié-Salpêtrière, APHP, Paris, France
ARTICLE INFO
Article history: Accepted 4 September 2024 Available online 5 October 2024
ABSTRACT
Background: Lymph node dissection improves adrenocortical carcinoma staging, but remains anatomi- cally poorly defined. This ambiguity stems from limited knowledge of the adrenals lymphatic network. This work aims to define lymph node dissection for adrenocortical carcinoma through a systematic re- view and anatomical study.
Method: First, an anatomical study was conducted on fresh cadavers by injecting blue dye into each adrenal gland before dissection. Concurrently, a systematic review of anatomical and clinical studies was performed, focusing on adrenals lymphatic network, lymph node dissection, and location of invaded lymph nodes in surgical series.
Results: Twelve adrenals from 6 cadavers were resected en bloc with a median of 3 lymph nodes (1.5-6) removed. Screening of 6,506 studies revealed (1) 18 anatomical studies on cadavers detailing a 3-stage compartmentalized adrenals lymphatic network with distinct right/left lymph nodes relays; (2) 4 clin- ical studies highlighting discrepancies in lymph node involvement in adrenocortical carcinoma patients compared with anatomical description of adrenals lymphatic network, notably: lower implication of celiac lymph node, preponderance of ipsilateral renal hilum lymph nodes, potential contralateral involvement; (3) 21 series of adrenocortical carcinoma surgery demonstrating the heterogeneity of lymph node dissection practice (22% ± 4% lymph node dissection rate), with an average of 2.7 ± 0.6 lymph nodes removed, already fewer than in our cadaveric study.
Conclusion: Synthesis of anatomical and clinical studies suggest the following lymph node dissection protocol during adrenocortical carcinoma resection: capsular, renal hilum, para-cava, and inter-aortic- cava lymph nodes (right adrenocortical carcinoma); and capsular, renal hilum, para-aortic, and inter- aortic-cava lymph nodes (left adrenocortical carcinoma).
@ 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Introduction
Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine neoplasm. Several prognostic factors associated with survival have been identified, such as tumor grade, Ki-67, age, cortisol hypersecretion, ENSAT (European Network for the Study of
Adrenal Tumor) stage,1,2 and quality of initial surgery performed in high-volume and tertiary centers, including lymph node (LN) positivity, tumor capsular injury, or margin-free resection.3,4
Complete surgical resection is the standard treatment for non- metastatic ACC, and the only hope for cure. If the laparoscopic versus open approach issue is still under debate,5 surprisingly oncological principles of adrenal resection have not been clearly defined and standardized.6,7 This is particularly true regarding lymph node dissection (LND) associated with primary ACC resec- tion, poorly studied with a great heterogeneity of published sur- gical series. LND is part of radical resection in a wide variety of
* Corresponding author: Sébastien Gaujoux, MD, PHD, Department of Digestive and Endocrine Surgery, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, Bat. Husson Mourier, 47-83 Avenue de l’Hopital, 75013, Paris, France.
E-mail address: sebastien.gaujoux@aphp.fr (S. Gaujoux).
cancer, improving staging, disease-free survival (DFS), and/or overall survival (OS).8 On the other hand, extensive LND might be associated with increased morbidity or be useless for tumors without lymphatic spread.9-11 Despite low-quality evidence, sur- gical literature seems to demonstrate an oncological benefit in performing systematic LND during the primary resection of ACC.12 Nevertheless, this practice is not technically standardized or sys- tematically performed. One of the main reasons for these diffi- culties is the lack of knowledge about the anatomical lymphatic drainage of the adrenal glands.
The aim of this research is to enhance our comprehension of the lymphatic drainage pathways of the adrenal glands and its clinical implications. This was done by an extensive anatomical study and a literature review of anatomical studies of the adrenal lymphatic network followed by clinical studies describing in vivo LN involve- ment in the context of ACC, and finally clinical implications and oncological outcomes associated with LND in the context of ACC.
Methods
Study design
This is a descriptive anatomical study carried out on fresh anatomical specimens (refrigerated only, not embalmed). All corpses were received after de vivo donation by the proband to be used for teaching and research purposes. Dissections were carried out in accordance with French legislation and institutional ethical guide- lines in the dedicated research structure of Paris Cité University. Body donation was based on free consent by the donor when they were alive, with a declaration of consent signed and registered by the institution (https://www.service-public.fr/particuliers/vosdroits/ F180). A donor card with a personal number was provided by the institution to the donor while alive. All dissections were done with the utmost respect for the deceased. This observational anatomical study was described according to the (Quality Appraisal for Cadav- eric Studies (QUACS) scale13 items for methodological clarity. Before dissection, the corpses were stored in a cold room at 4℃. The causes of death were not related to adrenal or renal disease and none of the specimens had undergone retroperitoneal surgery or dissection (neither during their lifetime nor after their death). A total of 6 adult corpses were dissected for this study.
Dissection protocol
The approach consisted of a median xypho-pubic incision with 2 transverse (cruciate) incisions to the lumbar fossae. Regarding the right adrenal compartment approach, the right colonic angle was lowered while the right hepatic lobe was reclined to the left after section of the suspensory ligaments between the right liver and the diaphragm. On the left, the colonic angle was lowered and the spleen and the tail of the pancreas medialized after transecting the phreno-splenic ligament in order to obtain a good exposure of the whole adrenal gland for the next steps of the procedure. The dye was prepared using 2.5% blue patente (Guerbet laboratory) to obtain, after dilution with physiological serum, a 1% diluted solu- tion. The dye injection was carried out in the same way on both sides, that is, using an insulin syringe with an 8-mm-long 30-G needle to inject a volume of 2 mL of the solution at 3 different lo- cations (upper, middle, and lower thirds) on the anterior side of the adrenal gland. The injection was performed slowly and carefully so as not to disrupt the fine lymphatic network. Finally, the injected area was massaged for about 20 seconds to potentiate the diffusion of the dye into the tissues. After an hour delay, a single-block right and left adrenalectomy was performed for each subject. The resection removed all peri-adrenal fatty tissue on both the left and
right sides until the upper pole of the kidney and the abdominal aorta and vena cava in regard of renal pedicles. Besides, the resected specimens were fixed in 40% formalin and stored for 7 days to obtain tissue firmness to facilitate future dissection. Then, a bleaching step was performed by immersing each specimen in a 200-mL solution of saline and hydrogen peroxide for 24 hours. The purpose of this step was to lighten the tissues and facilitate the recognition of the injected collectors and lymph nodes (LNs). Finally, we realized the dissection of each piece to look for LNs, colored or not, and count them.
Literature search
This review was conducted according to the principles of the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines.
A first literature search was conducted at the French National Library of Health (Bibliothèque Inter-Universitaire de Médecine BIUM, Paris, France) including medical theses to select anatomical works based on human body dissection and which described the lymphatic system of the the adrenal glands.
Then, a systematic literature was conducted in PubMed, Embase, and Cochrane Library Database from January 1, 2000, to September 31, 2023, and using the following search strategy for MeSH and non-MeSH: (lymph* [Title/Abstract] OR “lymph node*” [Title/Ab- stract] OR lymphnode* [Title/Abstract] OR “lymph* network” [Ti- tle/Abstract] OR adenopath* [Title/Abstract] OR lymphadenectom* [Title/Abstract] OR “lymph node dissection” [Title/Abstract] OR LND [Title/Abstract] OR “lymph node removal” [Title/Abstract] OR LNR [Title/Abstract]) AND (adrenal [Title/Abstract] OR suprarenal [Title/ Abstract] OR adrenocortical [Title/Abstract]). After identifying relevant title, abstracts were read, and eligible articles retrieved. A manual cross-reference search of the bibliography of all publica- tions retrieved was performed for relevant references, and the « related article > function in PubMed also used to identify studies that may have been missed in the database search. In order to perform a complete and descriptive analysis of the anatomy of the adrenal lymphatic system, we selected the clinical works that described the precise location of LN metastases in the context of ACC in order to obtain a “clinically relevant” anatomical description of the adrenal lymphatic system. Finally, we selected all published clinical articles that studied the LND in the context of ACC in order to recontextualize and put into perspective the anatomical analysis of the adrenal lymphatic system. Animal studies were excluded from our systematic research for clinical relevance, as non-English language articles and those with abstracts only. The search and sift process is presented in the PRISMA diagram in Figure 1.
Statistical analysis
All quantitative data are reported as median with interquartile range and qualitative data are reported as absolute value and per- centage. A graphical approach and Shapiro-Wilk test allowed us to retain the normality of the distribution of the number of LNs har- vested in this context (P = . 102). We therefore performed para- metric tests as Student’s and Pearson correlation tests according to the variables studied. We used the R 4.2.2 software for MacOS. All tests were 2-sided.
Results
Anatomical study
This study included 6 adult corpses, 3 men and 3 women. The median age was 88 years, and the median BMI was 22.4. The right
Identification
Studies identified Cochrane (n = 185) PubMed (n = 6092) Embase (n = 211) National Library (n = 18)
Studies removed before screening Duplicate (n = 244) Non-comparative studies* (n = 1638) Animal studies (n = 1843) Only abstract (n = 811) Non-english* (n = 947)
Screening
Studies screened (n = 1023)
Studies excluded Out of subject (n = 980)
Studies included (n = 43)
Included
Anatomical description of lymphatic network (n = 18)
« In vivo » description of lymphatic network (n = 4)
Lymph node dissection in clinical practice (n = 21)
* Except for studies from the National Library
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram.
and left adrenals of each subject were resected following the defined protocol. We analyzed 12 adrenals with blue dye injection.
Table I summarized both results and characteristics of the do- nors. In the whole series, the number of LNs removed from the resection pieces was 3 (1.5-6). There were more LNs removed in left adrenalectomies than in right adrenalectomies (5.5 vs 2.5). In both the right and left sides, we did not find any LNs stained by blue dye injection. No correlation was identified between the number of
| Series | |
|---|---|
| Age, yr, median (IQR) | 88 (80-93) |
| Gender, n (%) | |
| Male | 3 (50) |
| Female | 3 (50) |
| BMI (kg/m2), median (IQR) | 22.4 (20.8-24.2) |
| Lymph nodes harvested, median (IQR) | |
| All | 3 (1.5-6) |
| Right adrenals | 2.5 (1-3) |
| Left adrenals | 5.5 (2-6) |
| Lymph nodes stained, n (%) | 0 |
BMI, body mass index; IQR, interquartile range.
LNs collected on the right and on the left adrenal and the BMI (respectively P = . 381 and P = . 518) as well as with the age (respectively P = . 492 and P = . 60).
Review of the anatomical descriptions of the adrenal lymphatic network
In the anatomical literature, 18 studies describing the lymphatic drainage of adrenals glands in the human body were found and are summarized in Figure 2. The references are given in Appendix 1.
The oldest was the one of Huerman et al in 1774, followed by those of Mascagni et al and Cruikshank et al, which argued that the lymphatic vessels of the adrenals joined those of the kidney on the left and the lumboaortic nodes on the right. The description of the lymphatic network became more complex with the work of Le Baron Boyer et al, Bonnel et al, Maygrier et al, Soares Franco et al, and Cruveilhier et al showing that the drainage of the right adrenal gland goes to the para-cava and inter-aortic-cava LNs, whereas that of the left one goes to LNs close to the left pillar of the diaphragm. Finally, according to Arnold et al, on both sides, the drainage ends toward the thoracic duct, but Poirier et al observed just before the thoracic duct the presence of lymphatic collectors in the inferior and posterior mediastinum after directly crossing the diaphragm.
Legend
☒ Anatomical studies
Hidden et al. study (right adrenal)
Hidden et al. Study (left adrenal)
Diaphragmatic pillars & mediatinal LN
Celiac trunk LN
Right renal hilum LN
Left renal hilum LN
Para-cava & retro-cava LN
Para-aortic LN
Inter-aortico-cava LN
Grégoire et al in 1904 was the first to describe for each adrenal gland an anterior compartmentalization (called subpedicular) and a posterior compartmentalization (called suprapedicular). He argued that on the right as on the left, the anterior compartments drained toward the latero-aortic LN. The posterior compartments drained to the right and left diaphragmatic pillars and then crossed the diaphragm to the thoracic duct (right) and to a mediastinal LN (left) at the level of the ninth thoracic vertebra. The same findings were published by Bartels et al and Kumita et al. A second compartmentalization of the lymphatic drainage network of the adrenals was proposed by Delage et al in 1927 and Rouvière et al in 1932. Indeed, noting that the lymphatic vessels followed the ad- renal vascular pedicles, they defined 3 more levels of compart- mentalization. Thus, the superior collectors (satellite of the superior capsular and inferior diaphragmatic arteries) drained to- ward the celiac trunk, the middle collectors (middle capsular ar- teries) drained toward the origin of the superior mesenteric artery, and the last collector accompanied the main capsular vein and joined the lumboaortic LN.
In 1966, a study carried out by Merklin et al on 68 anatomical parts of adult autopsied subjects noted on the one hand that some lymphatics could reach the thoracic duct directly without LN relays, explaining distant metastasis, and on the other hand that regional LNs of the adrenal gland (first relays) were few in number, partic- ularly on the dorsal side.
In 1984, Hidden et al conducted a study of 25 unembalmed neonatal cadavers in which they injected a dye into the upper,
middle, and lower thirds of the anterior and posterior compart- ments of each adrenal gland. The dyes used (Prussian blue, emerald green, and scarlet red) were different for each cadaver between the right and left adrenals. In total, they were able to analyze 11 right and 14 left adrenals. Their results are summarized in Appendix 2 and confirmed the existence of proximal primary LN relays at the level of the penetration points of the capsular arteries, and the distribution of the collectors into 3 pedicles: upper, middle (the most inconstant), and lower (the most frequent). The first two appeared to have a predominantly celiac LN drainage whereas the lower pedicle seemed to drain to the lumbar lymphocenter. Moreover, there appears to be a close relationship between the adrenal lymphatics (especially the lower pedicle) and those of the kidney. Besides, the authors did not reaffirm Merklin’s findings on the presence of an adrenal collector directly joining the thoracic duct. On the contrary, Hidden et al systematically observed a middle capsular LN on the right or a posterior mediastinal LN on the left, interrupting this direct path. Finally, the authors never found any anastomosis between the lymphatic network of the adrenal gland and the diaphragm like Kumita’s work, or the liver or the contralateral adrenal gland.
In another adrenal anatomy description, Avisse et al described 3 pathways of collecting lymphatic vessels. On the right adrenal gland, the first pathway ended in the right latero-aortic LN near the celiac trunk. The second pathway also finished in the right latero- aortic LN but at the junction between the left renal vein and vena cava. The third pathway ended in the thoracic duct or in the
posterior mediastinal LN. Concerning the left adrenal gland, both first and second pathways ended in the left latero-aortic LN near the celiac trunk and left renal vein. The last pathway finished as the right side. It is important to note that all anatomical studies were performed on normal and not tumoral adrenal glands.
Review of the in vivo descriptions of the adrenal lymphatic network
In this second part of the adrenal lymphatic network review, 4 clinical studies describing in vivo LN involvement in the context of ACC were identified (Figure 3).
Reibetanz et al14 realized a retrospective study based on the cohort of patients from ENSAT registry. From the 971 patients in that cohort, they included 56 patients who had a first LN metastasis recurrence after primary resection for ACC ENSAT I-III with R0 resection and with at least 3 months of DFS. Among these 56 pa- tients, 57% (n = 32) had distant metastases also, in the following locations: pulmonary (n = 20), liver (n = 10), peritoneum (n = 8), bone (n = 2), and others (n = 5). At least half of the ACC resected,
both right and left, showed recurrence in the ipsilateral perirenal fat (particularly in the upper pole), without any recurrence in the contralateral side. In the resected right ACC (n = 20), the LN recurrence was observed for 35% (n = 7) in IAC, 30% (n = 6) in para- cava, 10% (n = 2) in renal hilum, 10% (n = 2) in para-aortic, and none in celiac trunk compartments. In resected left ACC (n = 36), the LN recurrence was observed for 22% (n = 8) in IAC, none in para-cava, 50% (n = 18) in renal hilum, 47% (n = 17) in para-aortic, and 6% (n = 2) in celiac trunk compartments. According to the 15 patients with an IAC recurrence (both left and right), only 1 had an isolated IAC recurrence. Moreover, near 50% of patients had LN metastases detected in the caudal compartments of the ipsilateral renal hilum, along the large vessels. Finally, 11% of the patients (n = 6) included underwent an intended LND during primary resection, with be- tween 4 and 6 LNs removed, all of which were negative. At least 3 of the 6 patients had a recurrence in an area that had already possibly been dissected during the primary adrenalectomy.
In the study by Polat et al15 discussing the place of adjuvant radiotherapy and area to target after ACC resection, they mentioned
Legend
Polat et al. Study (left adrenal)
Polat et al. Study (right adrenal)
· Reibetanz et al. Study (left adrenal)
Reibetanz et al. Study (right adrenal)
Sada et al. Study (left adrenal)
Sada et al. Study (right adrenal)
the distribution of LN recurrences. After right ACC, LN recurrences were mainly ipsilateral renal hilum, para-cava, and IAC. After left ACC, LN recurrences were ipsilateral renal hilum, para-aortic, and IAC. No LN involvement was observed in the celiac trunk or contralateral regions. Based on their observations, to prevent the risk of LN involvement, the authors suggested to irradiate the kidney hilum, the para-aortic and para-cava areas, and down to the aortic crest.
Sada et al16 conducted a retrospective study of 231 patients operated on for ACC. Among these, 14 patients had LN involvement. Positive LNs in the right ACC (n = 7) were as follows: 2 para-cava, 1 para-cava and renal-hilum, 1 IAC, 1 celiac trunk, 1 para-aortic, and 1 unknown. Positive LNs in the left ACC (n = 7) were as follows: 2 para-aortic, 2 renal-hilum, 1 para-aortic and left renal-hilum, and 1 unknown. No involvement of IAC, para-cava, or celiac trunk com- partments was described. Moreover, among the 231 patients, 55 underwent a resection for recurrent ACC, in whom 9 patients had LND and 2 had previous LND during primary resection. Positive LN locations for recurrent left ACC (n = 2) were 1 para-aortic and 1 para-aortic with renal hilum. Positive LN locations for recurrent right ACC (n = 7) were as follows: 2 IAC, 2 renal hilum, and 2 para- cava. Finally, no information was given regarding the perirenal fat in both sides, and no LN involvement was observed in the contra- lateral renal hilum area.
Lastly, Gerry et al17 realized a retrospective and multicenter study on 120 patients operated on for an ACC. Of these, 32 under- went an LND (27%). Harvested LNs concerned IAC for 22 patients (in
whom 27% were positive), renal hilum for 18 patients (in whom 44% were involved), retroperitoneal for 5 patients (in whom 40% were positive), peripancreatic for 4 patients (in whom 25% were positive), and celiac trunk for one patient (without positive LN) and porta hepatis for another (positive LN).
LND performed in clinical practice
Table II summarizes the selected published surgical series dealing with LNDs in ACCs that were operated on. Overall, 21 ar- ticles were selected according to the criteria defined in the Method section.
Overall, the series selected represent more than 21,000 patients who underwent ACC resection and for whom data on LNDs were provided. The definition of LND varies according to the authors. Some studies stipulate that a minimum of ≥5 LNs must be har- vested21,23,24; others set the threshold at >4 LNs.25 In some series, the presence of at least >1 LN in the pathology specimen was considered adequate,26,28,30 whereas certain studies defined LNDs as performed based on the surgeon’s intention to carry out the procedure,16,17,29 regardless of the number of LNs found in the pa- thology sample. Finally, the majority of studies assessing LNDs in ACC do not specify any definition.18-20,22,27,31-36
On average, the rate of LND during ACC resection was 22% + 4%, with some studies reporting rates exceeding 30%18 and others less than 10%.23-25,31 When LND was performed, the number of LNs harvested per patient varied between 230 and 5.517,21,32 on average,
| Authors (yr) | Data-base | N | Follow-up (mo) | MVR | Definition of LND | LND (%) | Number of LN harvested | pN+ | LND and survival* |
|---|---|---|---|---|---|---|---|---|---|
| Icard et al (2001)18 | AFCE | 253 | NA | Yes | NA | 32.5% | NA | NA | No OS benefits |
| Bilimoria et al (2008)19 | NCDB | 2,920 | 24 | Yes | NA | 17.6% | NA | 26.5% | NA |
| Lombardi et al (2012)20 | Multi- centric | 278 | 34.4 | Yes | NA | 17.1% | NA | 42% | NA |
| Reibetanz et al (2012)21 | German registry | 283 | 39-59 | Yes | ≥5 | 16.6% | 5.5 | 25.5% | Benefits only on DFS |
| Tran et al (2013)22 | SEER | 280 | NA | Yes | NA | 26% | NA | 35% | Benefits only on DFS for pT4 |
| Alanee et al (2015)23 | SEER | 1,037 | NA | Yes | ≥5 | 5.6% | NA | 31% | Benefits only on DFS |
| Saade et al (2015)24 | SEER | 259 | 64-62 | Yes | ≥5 | 6.2% | NA | 44% | No OS or DFS benefits |
| Gerry et al (2016)17 | Multi- centric | 120 | 25.4-26 | Yes | Surgeon intent | 27% | 5.5 | 25% | OS benefits (HR 0.17, 95% CI 0.1-0.6) |
| Nilubol et al (2016)25 | SEER | 1,525 | 29-25 | Yes | ≥4 | 8.4% | NA | 33% | No DFS benefits |
| Panjwani et al (2017)26 | NCDB | 827 | NA | No | ≥1 | 19% | 3 | 22% | OS benefits if >4 LNs removed |
| Wang et al (2017)27 | SEER | 749 | NA | Yes | NA | 20.1% | NA | 64.8% | No OS benefits |
| Tella et al (2018)28 | NCDB | 2,305 | NA | Yes | >1 | 24.6% | NA | 45.8% | Stage I-III: worsened OS; but Stage IV: OS benefits |
| Marincola Smith et al | Multi- | 167 | 37.5 | Yes | Surgeon | 22% | 3.4 | 33% | OS benefits (HR 0.29, 95% CI 0.1-0.8) |
| (2018)29 | centric | intent | |||||||
| Deschner et al (2020)30 | NCDB | 897 | 37.5 | No | ≥1 | 16.4% | 2 | 16,3% | No OS benefits |
| Sada et al (2020)16 | SEER | 1,307 | NA | Yes | NA | 23,1% | 5.5 | 25.2% | NA |
| Delozier et al (2021)31 | NCDB | 196 | 29.9 | Yes | NA | 6.6% | NA | NA | NA |
| Sada et al (2022)32 | Single- | 231 | 24 | Yes | Surgeon intent | 22% | 3.5 | 6% | NA |
| center | |||||||||
| Holoubek et al (2022)33 | NCDB | 3,567 | 27.6 | Yes | NA | 16% | NA | NA | NA |
| Akinkuotu et al (2022)34 | NCDB | 2,553 | 33 | Yes | NA | 23% | NA | NA | Worsened OS (HR 1.30, 95% CI 1.1-1.5), except in children |
| Ginsburg et al | NCDB | 776 | 38.9 | NA | NA | NA | 3 | NA | NA |
| (2022)35 | |||||||||
| He et al (2023)36 | SEER | 876 | 52-58 | NA | NA | 17% | NA | NA | No OS benefits |
| Overall | - | 21,406 | - | - | - | 22% ± 4% | 2.7 ± 0.6 | 29% ± 12% | - |
ACC, adrenocortical carcinoma; AFCE, French Association of Endocrine Surgery; DFS, disease-free survival; HR, hazard ratio; LN, lymph node; LND, lymph node dissection; MVR, multivisceral resection; NA, missing information; NCDB, National Cancer Database; OS, overall survival; pN+, LN involved; SEER, Surveillance, Epidemiology, and End Results. * Independently of whether the LN harvested were invaded or not.
t Mean + standard deviation.
with an overall average of 2.7 + 0.6, although most studies did not report this figure. 3,18-20,22-25,27,28,31,34 Among the LNs removed, the average number of positive LNs was 29% + 12% in these series.
Fourteen studies evaluated the association between LND and survival (OS and DFS), regardless of whether the LNs sampled were positive or not. Five studies found no statistical association be- tween OS and LND.18,24,25,27,30 Conversely, in the study by Gerry et al,17 this association was positive (hazard ratio 0.17, 95% confi- dence interval [CI] 0.05-0.61), as in the work of Marincola Smith et al29 (HR = 0.29, 95% CI 0.11-0.78). LND appeared to be associated with a benefit on OS in the study by Panjwani et al26 only if more than 4 LNs were removed. However, 2 studies demonstrated that LND was significantly associated with a poorer OS except in chil- dren according to Akinkuotu et al34 and except in stage IV ACC according to Tella et al,28 in whom OS was increased. Regarding DFS, 3 studies showed a positive association between LND and DFS,21-23 although this association was not found in the studies by Saade et al24 and Nilubol et al.25
Discussion
Significant progress has been made in the medical management of ACC with prospective randomized controlled trials on combi- nation chemotherapy,37 the setting of adjuvant mitotane therapy,38 the future results of ADIUVO-2 (NCT03583710), and the place of local therapies such as postoperative radiotherapy.39 However, surgical treatment, the only hope for cure, remains poorly studied
with a low level of evidence, especially regarding LND. Optimizing LND means first understanding its network, in order to adapt its surgical realization.
Our anatomical study results indicate that staining the adrenal lymphatic drainage with subcapsular injection of patent blue dye was not straightforward. This difficulty is likely due to the fragility of the adult adrenal gland lymphatic network, particularly in deceased subjects, a challenge also noted in several other anatomical studies of the adult lymphatic network.40 Studies on pediatric bodies seem to show better results (Hidden et al). Nevertheless, our study also shows the very low numbers of LNs surrounding the adrenal gland, which is concordant with other anatomical and clinical studies. It seems likely that the adequate number of LNs to be harvested for an appropriate staging is be- tween 4 and 6.
There is some concordance between anatomical and clinical studies on the locations of LN involvement (Figure 4). Both recog- nize the importance of the lumboaortic and perirenal fat areas in the lymphatic drainage of the adrenal glands. These studies also agree that the lymphatic drainage networks of the right and left adrenals differ: the right adrenal drains mainly to the para-cava and IAC nodes, whereas the left adrenal mainly joins the para-aortic LN. Furthermore, connections between the adrenal lymphatic network and the ipsilateral renal hilum network, more frequent on the left side, were found in several studies (Cruikshank et al, Bartels et al, and Hidden et al). This prevalence on the left side is also observed in clinical studies, supporting the relevance of a left renal hilum
Legend
LN for left adrenal gland
0% LN for right adrenal gland
Summary of LN in anatomical studies
Diaphragmatic pillars & mediatinal LN
Celiac trunk LN
Right renal hilum LN
Left renal hilum LN
Para-cava & retro-cava LN
Para-aortic LN
Inter-aortico-cava LN
LND in left ACC. The preferential drainage of the inferior adrenal pedicle by the left renal hilum lymphocenter may explain the earlier marking of the left adrenal gland’s posterior mediastinal LN (Hidden et al), rather than direct drainage to the thoracic duct as suggested by other authors (Merklin et al).
However, discrepancies also exist (Figure 4). First, anatomical studies show drainage into the thoracic duct and various medias- tinal or diaphragmatic LN, whereas clinical studies do not report any recurrences in these areas. On the contrary, LN invasion seems to predominantly occur in the ipsilateral renal hilum, a network documented in anatomical studies and influenced by the collector pedicles involved (mainly the inferior, according to Hidden et al in Appendix 2). Secondly, anatomical studies also highlight the central role of the celiac lymphocenters for both right and left adrenals (>90% of observations in Appendix 2), a preponderance less pro- nounced in clinical studies, with involvement ranging from 0% to 14%.14-17 Third, correlating anatomical descriptions with clinical relevance can be challenging. Anatomical studies focus on varia- tions in networks based on adrenal gland compartmentalization and the collecting pedicles, but such granularity may not be clini- cally relevant. Differences between anatomical and clinical studies might also stem from a lack of standardization in LN staging and the use of diverse terminologies, as demonstrated in the Gerry et al study,17 which refers to retroperitoneal and peripancreatic LN areas, potentially causing misinterpretations. All these discrep- ancies might also be due to reverse flow in the lymphatic network caused by 2 factors. On the one hand, it could be caused by the obstruction from LN invasion of proximal relays,7 a discrepancy not specific to ACC and also observed in other adrenal pathologies like childhood neuroblastoma.41 On the other hand, because of the size, often >10 cm, of the ACC at the time of diagnosis, the lymphatic drainage pathways can be affected. Lastly, anatomical studies agree in refuting the existence of contralateral lymphatic collectors. However, Reibetanz et al14 observed the opposite, with 5.6% of right renal hilum LN recurrence after left ACC, and 10% of left para-aortic LN recurrence after right ACC, albeit in a minority of cases. It cannot be denied that such a result can, in part, be explained by post- operative remodeling and dissemination. However, in the 56 pa- tients of Reibetanz’s cohort, only 6 patients had undergone LND at the time of the primary tumor resection, and contralateral LN recurrence occurred in only 1 of these 6 patients. Therefore, there are probably other explanations than postoperative remodeling. Furthermore, several data in the literature have confirmed the ex- istence of contralateral LN involvement in various cancers, 42-44 and the adrenal lymphatic network is probably no exception.
The literature largely concurs on the necessity for systematic LND. Table II indicates an association between LND performance and improved survival (both OS and DFS), despite some divergence in findings. In the meta-analysis by Hendricks et al,12 LND was associated with a higher DFS in patients with nonmetastatic ACC (hazard ratio 0.42; P < . 001) without increasing mortality risk or length of hospital stay. The importance of LND is underscored by the average 29% positive LN rate in the literature (Table II) although this rate is likely underestimated. In fact, to support this argument, King et al45 reported an LN involvement rate of 73% in 29 autopsies of patients with ACC. Tseng et al4 also found that 17.5% of clinical N0 patients upstaged to pathological N1 disease post-LND, suggesting significant understaging without LND. Conducting an LND would enable a more accurate assessment of LN status in ACC. This in- formation seems all the more crucial as the significance of LN metastases in ACC prognosis was notably highlighted in the study of Libé et al,1 which established that the prognostic impact of LN metastases was comparable to that of distant metastases. They suggested a refined subdivision of stage IV in the ENSAT classifi- cation into 3 distinct subcategories (IVa, IVb, and IVc) of a modified
ENSAT (mENSAT) classification. This revised classification would more comprehensively account for the number of organs involved recognizing the LN as an individual organ. Today, despite aggressive surgical resection of ACC, local and distant recurrence rate after R0 surgery remains as high as 50%-80%, potentially because of the lack of an accurate identification of the LN stations for the LND. With these considerations in mind, the prospective study LACC (NCT05763524) is currently under way to assess the impact of LND on oncologic outcomes in ACC.
However, LND suffers from lack of standardization in other areas. First, the definition of what constitutes an LND for the ACC varies greatly among studies (Table II). Indeed, some define LND as the removal of at least 5 LNs, whereas others propose lower numbers or even the surgeon’s sole intention. Nevertheless, Rei- betanz et al21 suggested that removing more than 5 LNs could reduce the risk of local recurrence and improve DFS. Finally, Pan- jwani et al26 found that a threshold of 4 LNs examined in N0 pa- tients improved OS (P =. 02). Second, as of this writing, there is no clear consensus on which LND technique to adopt, and several LND protocols have been proposed. In 2012, Gaujoux et al7 suggested an LND protocol consisting of systematically resecting the LNs of the celiac trunk, renal hilum on the ipsilateral side of the adrenal tu- mor, para-aortic and para-cava. The Italian consensus of 201646 joined the same proposition and a similar protocol was also sug- gested21: removing all LNs between the lower edge of the liver, the edge of the inferior vena cava, and the renal pedicle on the right side; on the left side, they recommended removing LNs between the diaphragmatic crus, the edge of the aorta, and the renal pedicle. Finally, in the consensus guidelines of 2017,5 the proposed LND included at least the renal hilum and periadrenal fat LNs. The same recommendation for LND was proposed in 2020 by the ESMO- EURACAN (European Society for Medical Oncology and the Euro- pean Reference Network for Rare Adult Solid Cancers) Clinical Practice Guidelines47 and by ESE-ENSAT (European Society of Endocrinology and the European Network for the Study of Adrenal Tumors) guidelines.48 It is probably these 3 latter protocols that are most often used. In fact, when we look at the number of LNs removed in the studies where this is mentioned (Table II), the average number of LNs harvested was around 2.6. This result is quite similar to the one found in our anatomical study of 3 (1.5-6). This suggests that in most cases, only an en bloc resection was performed (as recommended in the last consensus guidelines),5 removing only the periadrenal fat LN until the upper pole of the kidney and the abdominal aorta and vena cava in regard of renal pedicles, as we have done, without performing more extensive LND up to the central lymphocenters.
There are several difficulties to consider in developing a consensus LND concerning its surgical feasibility. First, although several anatomical studies confirm the retro-cava drainage of the right adrenal gland, the LND of this area is technically difficult and can be associated with subsequent morbidity. Second, a similar reasoning can be made about the risk of invasion of LN of the posterior mediastinum for which a thoracic approach is not conceivable in the first instance. A potential option would be the use of adjuvant radiotherapy, in high-risk patients for LN involve- ment, for these difficult-to-access locations, especially as few studies suggested the beneficial effect of adjuvant radiotherapy on OS and DFS.15,49 In addition, there are atypical LN target locations. This is notably the case for the primary iliac region, found after dye injection in the inferior compartment of the right adrenal gland by Hidden et al. A similar result was found in a clinical study in 20% of cases after dye injection in the left adrenal gland,41 as well as in the Reibetanz et al study where 5.6% of left ACC LN recurrences were at the aortic bifurcation.14 Moreover, it is also important to underline that LN involvement in ACC can differ according to ACC molecular
classification, making general recommendations on LND even more difficult. Lastly, this also questions the laparoscopic approach for ACC, which might make it more technically difficult and less likely to accomplish an LND. Indeed, in the studies reporting LND for ACC (Table II), only 5% of procedures were performed via a minimally invasive approach (laparoscopic and robot-assisted). In contrast, of the 26 studies reporting laparoscopic surgery for ACC in the recent review by Langenhuijsen et al,50 only 9 reported the realization of an LND.
In light of the data from the clinical and anatomical studies analyzed, and based on a benefit-risk ratio, we could propose a new, more coherent and pragmatic LND protocol as summarized in Figure 5: for the right ACC, capsular, ipsilateral renal hilum, para- cava, and inter-aortic-cava; and for the left ACC, capsular, ipsilat- eral renal hilum, para-aortic, and inter-aortic-cava. Dissection of the celiac trunk LN seems excessive in view of the results in the literature for both the right and left ACC. Concerning the right renal hilum area in the case of a right ACC, few invaded LNs seem to have been described in in vivo studies. Nevertheless, given the anatomical proximity of this region to the right capsular and para- caval areas, the density of LNs described in this region in anatomical studies, and its intermediate location between the right adrenal gland and the central LN, resection of this area during LND seems relevant. Furthermore, the low number of recurrences of LNs in the lower pole of the ipsilateral perirenal fat14 does not give us suffi- cient reason to extend the LND to the entire perirenal fat. The minimum number of LN to be removed is difficult to determine. In view of the desire for extensive LND, limiting the number to 3 (and therefore only to the perirenal fat) seems insufficient, whereas there is evidence to support the positive impact of ≥5 LNs on survival.
In conclusion, LND increases the staging of ACC but its positive influence on OS is still controversial. The difficulty lies in the need
to define an effective and reproducible LND protocol; however, such a proposal is a challenge with the current state of knowledge for several reasons. First, missing data is very important, and results of published series are highly heterogenous in terms of survival after LND, of type of LND performed, and of the number of LNs removed. Second, in view of the sometimes-contradictory results between anatomical and clinical studies, it is essential to carry out new in vivo studies to obtain a complete and reliable mapping. Indeed, as shown by our anatomical study and others, the use of post-mortem adult subjects does not seem to be suitable to answer the problem.
Funding/Support
This research did not receive any specific funding from any agencies in the public, commercial, or not-for-profit areas.
Conflict of Interest/Disclosure
The authors have no conflicts of interests or disclosures to report.
CRediT authorship contribution statement
Charles de Ponthaud: Writing - review & editing, Writing - original draft, Methodology, Investigation. Soumaya Bekada: Re- sources, Funding acquisition, Data curation. Camille Buffet: Visu- alization, Validation, Supervision. Malanie Roy: Visualization, Validation, Supervision. Anne Bachelot: Writing - review & edit- ing, Visualization, Validation, Supervision. Amine Ayed: Writing - review & editing, Visualization, Validation. Fabrice Menegaux: Writing - review & editing, Visualization, Validation, Resources,
A
B
Right ACC
Left ACC
Conceptualization. Sébastien Gaujoux: Writing - review & editing, Writing - original draft, Visualization, Validation.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at [https://doi.org/10.1016/j.surg.2024. 09.008].
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