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Review – Adrenal Glands

Surgical Management of Adrenocortical Carcinoma: Impact of Laparoscopic Approach, Lymphadenectomy, and Surgical Volume on Outcomes—A Systematic Review and Meta-analysis of the Current Literature

By: Johan Langenhuijsena , Alison Birtleb, Tobias Klattec, Francesco Porpigliad and Marc-Oliver Timsite

EU Focus, Volume 1 Issue 3, February 2016, Pages 241-250

Published online: 01 February 2016

Keywords: Adrenocortical carcinoma, Laparoscopy, Lymph node dissection, Surgical volume

Abstract Full Text Full Text PDF (888 KB) Patient Summary

Abstract

Context

Controversy exists regarding the choice for surgical approach and the role of lymph node dissection (LND) in adrenocortical carcinoma (ACC) treatment. ACC surgery is increasingly advocated to be performed in specialist referral centres.

Objective

To review systematically the evidence of oncologic outcomes for ACC surgery by open adrenalectomy (OA) or laparoscopic adrenalectomy (LA), and for concomitant LND. The influence of surgical volume is also analysed.

Evidence acquisition

A systematic review of Ovid Medline, Embase, and the Cochrane Library was performed in June 2015 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Twenty-six publications were selected for inclusion in the analysis. Meta-analyses were performed when appropriate.

Evidence synthesis

Included studies reported on oncologic outcomes after surgical treatment of ACC (11 studies), compared different surgical approaches (7 studies), evaluated the role of LND (3 studies), and analysed the effect of surgical volume on outcome (5 studies). From the available studies and the meta-analysis, no differences were found in the rate of positive surgical margins, disease-free survival, and overall survival between OA and LA in localised disease. In patients with histologically proven positive lymph nodes, a shorter time to recurrence was seen when no proper LND was performed. A trend for better recurrence-free survival and disease-specific survival after LND was found. In high-volume centres, more aggressive and open surgery was performed. In low-volume centres, higher local recurrence and distant metastases rates, and a shorter time to recurrence were seen. Our findings are limited due to the low level of evidence of selected studies, patient and disease heterogeneity, and heterogeneous surgeon populations.

Conclusions

After adequate clinical staging for localised disease, LA is as effective and oncologically safe as OA, as long as oncologic principles are respected. LA should be performed by surgeons with extensive experience in laparoscopic adrenal surgery in high-volume centres. Patients with locally advanced disease and metastatic disease, for debulking purposes, should be operated on extensively with open surgery with adequate margins and concomitant LND to optimise staging, which may contribute to survival in locally advanced disease.

Patient summary

Laparoscopic surgery for localised adrenocortical carcinoma is safe and effective when performed by expert surgeons in high-volume centres. Patients with more extensive tumours should be operated with open surgery; lymph node dissection is mainly applied to determine the stage of the disease.

Take Home Message

Laparoscopic surgery for localised adrenocortical carcinoma is safe and effective when performed by expert surgeons at high-volume centres. Patients with more extensive disease should be operated with open surgery, and lymph node dissection is indicated mainly for staging.

Keywords: Adrenocortical carcinoma, Laparoscopy, Lymph node dissection, Surgical volume.

1. Introduction

Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. The estimated incidence is 1 per million people [1] and [2], with an estimated 5-yr survival rate of 16–47% varying with tumour stage [1], [3], [4], and [5]. Historically, open surgery was the gold standard for clinically suspected ACC by lumbotomy, laparotomy, or the thoracoabdominal approach. Since the early 1990s, laparoscopy has emerged for benign adrenal tumour surgery [6] and progressively became the standard. The advantages of minimally invasive adrenal surgery are clear and include less blood loss, a shorter recovery time, and reduced pain after surgery [7]. Thus urologists have been tempted to apply laparoscopic surgery to ACC management for many years, especially in localised disease, classified by the European Network for the Study of Adrenal Tumours (ENSAT) as stages 1–2 (Table 1) [5]. However, it remains under debate whether laparoscopic adrenalectomy (LA) is oncologically safe and equally effective as open surgery. The advantages of laparoscopy are only justifiable if oncologic outcome is not adversely affected by the approach. Furthermore, the care for ACC patients and oncologic care in general is increasingly handled by experts in high-volume centres (HVCs) of expertise [8]. The aim of this systematic review was to evaluate the oncologic outcome of ACC treatment for different surgical approaches including the role of concomitant lymph node dissection (LND). The level of evidence (LE) to support minimal invasive surgery for ACC and the effect of surgical volume on outcome are also analysed.

Table 1 Classification of the European Network for the Study of Adrenal Tumours

StageTNM
1≤5 cm00
2>5 cm00
3Local infiltration/invasion
Any T
0
+
0
0
4Any TAny N+

2. Evidence acquisition

2.1. Search strategy

A systematic Ovid Medline, Embase, and Cochrane Library search from 1990 to the present was performed on June 3, 2015. Supplement 1 describes the complete free-text search terms and the search strategy. A hand search was performed from selected articles for cited references.

2.2. Inclusion criteria

The lead author participated in the design of the search strategy and inclusion criteria. The procedure for evaluating records identified during the literature search followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria (Fig. 1) [9]. The final list of included articles was selected with the consensus of all collaborating authors, verifying that these articles met the inclusion criteria.

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Fig. 1 Flow diagram of evidence acquisition in a systematic review on surgical treatment for adrenocortical carcinoma and the role of lymph node dissection and surgical volume.

2.3. Study eligibility

No randomised trials or prospective studies for the surgical outcome of ACC exist. Therefore, cohort studies and large retrospective series (LE 2b according to the Oxford Centre for Evidence-based Medicine) were considered relevant to this review if they assessed the following: oncologic outcome of different surgical approaches (ie, open surgery, laparoscopy, and/or robotic), a comparison of oncologic outcome among surgical approaches, the role of concomitant LND, and surgical volume. These criteria were limited to studies published in the English language, original studies, and meta-analyses. Review articles, meeting abstracts, editorials, and commentaries were excluded. In addition, cohort studies with <20 patients of curative surgery for ACC were not accepted for inclusion. In studies reporting on the same or overlapping series, the latest study was selected, unless different end points were investigated or different subgroup analyses were performed.

2.4. Outcome measures and statistical analysis

Meta-analyses were performed to compare oncologic outcomes of open adrenalectomy (OA) and LA when appropriate. The points of interest included positive surgical margin rate, overall survival (OS), and disease-free survival (DFS). Numbers, proportions, hazard ratios (HRs) with confidence intervals (CIs), and numbers of events were extracted. If data were not reported directly, values were estimated according to Parmar et al. [10]. Multivariable HRs were preferred over univariable HRs. One study [11] only provided an HR for disease-specific survival (DSS). Because there was only one death not related to ACC, this HR was used to estimate differences in OS. The study heterogeneity was assessed using I2 statistics and the Cochran Q test. These analyses revealed relevant heterogeneity, so random effects models were used as the default. Publication bias was assessed with funnel plots and Egger tests for asymmetry. Analyses were performed using Stata software v.11 (Stata Corp., College Station, TX, USA).

2.5. Included studies

From the search, 1078 manuscripts were identified. Of these, 26 original articles were selected for inclusion [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], and [36] (Fig. 1 and Table 2). The primary outcomes were OS (n = 10), DFS, and OS (n = 14), DSS with and without LND (n = 1), and risk for peritoneal carcinomatosis (n = 1). Secondary outcomes were prognostic factors for outcome (n = 5), complications (n = 1), surgical volume (n = 1), and surgical technique (n = 3). Of note, two publications were secondary reports of previously published studies [12] and [20]. Four other publications came from the same centre [15], [16], [27], and [28]. In addition, no meta-analyses were identified or included in this systematic review.

Table 2 Descriptive baseline characteristics of selected original publications identified by systematic literature review: study period, sample size, population, follow-up, inclusion criteria, end points, and operating technique

StudyPeriodnSingle centre or multicentreFollow-up, moInclusion criteriaStudy end pointsOperating technique, %, OA; LA
Comparison of oncologic results in OA and LA
Donatini et al. [13]1985–201134Single57–80R0 resection, stages 1–2, <10 cmDFS, OS, complications62; 38
Fossa et al. [17]1998–201132Single29Stages 1–3DFS, OS47; 53
Mir et al. [19]1993–201144Single26All stagesDFS, OS, technique59; 41
Lombardi et al. [20]1903–2003156Multi42R0 resection, stages 1–2DFS, OS, technique81; 19
Miller et al. [21]1905–2005156Multi19–29.5Stages 1–3DFS, OS, technique71; 29
Brix et al. [11]1996–2009152Multi39Stages 1–3, ≤10 cmDSS, OS77;23
Porpiglia et al. [26]2002–200843Multi35R0 resection, stages 1–2DFS, OS58; 42
General oncologic outcome in other series
Else et al. [12]1979–2013389Single25.6All stagesDFS, OS, prognostic factors71; 26
Cooper et al. [16]1993–2012302Multi34All stagesDFS, OS, prognostic factors85; 15
Leboulleux et al. [25]2003–200964Single35All stagesRisk factors for peritoneal carcinomatosis91; 9
Grubbs et al. [27]1991–2008218Multi88All stagesDFS, OS92; 8
Gonzalez et al. [28]1991–2004160Multi28All stages, complete resectionDFS, OS96; 4
Schulick et al. [30]NA107Single28All stagesOSNA
Crucitti et al. [31]1965–1993129MultiNAAll stagesOS99; 1
Zografos et al. [32]1950–199053SingleNAAll stagesOS100; 0
van Heerden et al. [33]1960–198062SingleNAAll stagesOS100; 0
1981–199031
Soreide et al. [35]1970–198499; 61, surgeryMulti>6 yrAll stagesOS100; 0
Grondal et al. [36]1974–198354; 38, surgeryMulti0.1–14 yrAll stagesOS100; 0
Role of LND
Reibetanz et al. [23]1981–2009283Multi40R0, stages 1–3DSS with/without LND, DFS91; 9
Icard et al. [29]1978–1997253MultiNAAll stagesOS100; 0
Icard et al. [34]1979–199141SingleNAAll stagesOS100; 0
Influence of surgical volume on oncologic outcome
Gratian et al. [14]1998–20112765Multi>60All stagesOS, surgical volume66–80;17–24
Ayala-Ramirez et al. [15]1998–2011275Single2.7 yrAll stagesDFS, OS, prognostic factors89; 11
Kerkhofs et al. [18]1999–2008139Multi>12All stagesOSNA
Hermsen et al. [22]1965–2008149Multi25Stages 1–3DFS, OS, prognostic factors95; 5
Lombardi et al. [24]1903–2003263Multi34All stagesDFS, OS, prognostic factors87; 13

DFS = disease-free survival; DSS = disease-specific survival; FU = follow-up; LA = laparoscopic adrenalectomy; LND = lymph node dissection; NA = not applicable; OA = open adrenalectomy; OS = overall survival.

3. Evidence synthesis

3.1. Comparison of oncologic results in open and laparoscopic adrenalectomy

Several retrospective studies were published in which the oncologic outcome of ACC after OA and LA was directly compared [11], [13], [17], [19], [20], [21], and [26]. In general, patient numbers were small, and follow-up was short to intermediate with a range of 19–80 mo. Patient demographics and tumour characteristics were heterogeneous.

Four retrospective observational studies that did not exclude patients with R1/2 resection compared the rate of positive surgical margins between both procedures [11], [17], [19], and [21]. There was considerable heterogeneity between studies (I2 = 50.4%), with a positive margin rate ranging from 16% to 45%. In the meta-analysis, there were no differences in the positive surgical margin rate in patients treated with OA or LA (pooled OR: 1.16; p = 0.7; Fig. 2A). No evidence for publication bias was revealed on the funnel plot (Fig. 3A) or the Egger test (p = 0.86).

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Fig. 2 Forest plots for (A) positive surgical margin rate, (B) overall survival, and (C) disease-free and progression-free survival of studies comparing laparoscopic adrenalectomy and open adrenalectomy.CI = confidence interval; HR = hazard ratio; OR = odds ratio.

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Fig. 3 Funnel plots of publication bias for the rate of (A) positive surgical margins, (B) overall survival, and (C) disease-free and progression-free survival.HR = hazard ratio; OR = odds ratio; SE = standard error.

Three studies specifically outlined the results for ENSAT stages 1–2 patients (localised disease) after negative surgical margins [13], [20], and [26]. Donatini et al. [13] reported no differences in OS, DFS, and recurrence in a single-centre study. Baseline tumour characteristics and the number of patients with adjuvant mitotane treatment were similar between groups. In a multicentre study by Lombardi et al. [20], matching groups were compared. Although more often LNDs were performed in the OA group (3% vs 18%), the local recurrence rates (21% vs 19%) and time to recurrence (29 vs 27 mo) were similar. DFS and OS were not statistically different. The authors concluded that the operative approach did not influence outcome as long as oncologic principles were respected. Porpiglia et al. [26] showed in a multicentre study that in well-matched groups with similar rates of adjuvant treatment of mitotane, both local and distant recurrences were comparable, and no peritoneal or port-site metastases occurred. Recurrence-free survival (RFS) (median: 23 vs 18 mo) and 3-yr survival (100% vs 84%; median survival not reached) were not significantly different between OA and LA (Table 3).

Table 3 Descriptive baseline characteristics of selected original publications identified by systematic literature review: stage, size, survival, and treatment

StudyStage, %
1, 2, 3, 4
Size, cmDFS per stage, 1, 2, 3, 4, moEstimated DFS at 5 yr, %OS per stage, 1, 2, 3, 4, moEstimated OS at 5 yr, %LND, %Local/peritoneal recurrence, %Positive margin or rupture, %Adjuvant therapy, %
Comparison of oncologic results in OA and LA
Donatini et al. [13]Only stage 1–25.5–6.846, LA; 47, OA6585, LA
81, OA
85NA7.6, LA; 9.5, OA4.7, OA62, LA; 71, OA
Fossa et al. [17]0–6, 47–71, 24–53, –8–138–150–4037–10420–60NA35, LA; 40, OA20–2913
Mir et al. [19]54, stage 1–2; 46, stage 3–47–13NA58, LA; 54, OA, (2 yr DFS)NA39, LA; 60, OA, (2 yr OS)45NA; 1, LA3841
Lombardi et al. [20]Only stage 1–27.7–948, OA; 72, LA38, OA; 58, LA60, OA; 108, LA48, OA; 67, LA3, LA;18, OA19, OA; 21, LA032, OA; 30, LA
Miller et al. [21]2.5, 54, 44, –7.4–12
11.7, LA; 29.5, OA
4, LA; 14.6, OA
NA
51, LA; 103, OA
NANA36, OA/R0; 65, LA/R016, OA; 30, LANA
Brix et al. [11]8–34, 55–60, 55–69, –6–8NA40, OA; 62, LANA63, LA; 52, OA after FU of 39 moNA315–2723
Porpiglia et al. [26]12–20, 80–88, –, –9–10.518–2338–45, (3 yr DFS)NA84–100, (3 yr OS)NA24, OA; 33, LANA60–66
General oncologic outcome in other series
Else et al. [12]3, 43, 28, 2911.837, 19, 8, –28, 21, 8, –57, 74, 30, 1340, 58, 24.5, 5.7NANANA40
Cooper et al. [16]1–20, 43–52, 22–35, 0–228–1210–205–18, corrected for T46–11040–50, corrected for TNA20–549–2817–37
Leboulleux et al. [25]3, 50, 11, 3313NANANANA25233595
Grubbs et al. [27]32–45, stage 1–2; 52–57, 4–11121312–484740–62NANA11–3110
Gonzalez et al. [28]89, stage 1–3; 11131310, OA4342, OANA43, OA; 50–83, LANANA
Schulick et al. [30]5, 46, 11, 3914NANA101, stage 1–2, vs 15, stage 3–437NANANANA
Crucitti et al. [31]49, stage 1–2; 33, 18NA16.5NA2335NA11NA17
Zografos et al. [32]11, 13, 21, 5511–14NANA46, 84, 8, 719NA28NANA
van Heerden et al. [33]1.6, 33, 13, 5312NANA25, 34, 21, 419NANANANA
0, 52, 13, 3513NANANA39NANANA52
Soreide et al. [35]30, stage 1–2; 18, 52NANANA<9, (stage 3–4)16, (6 yr OS); 4.6, (10 yr OS)NANANANA
Grondal et al. [36]0, 24, 11, 6513–15NANANA19 (x, 54, 16, 6) vs 45 (radical surgery)42NA42NA
Role of LND
Reibetanz et al. [23]8, 61, 31, 010–129.9, no LND; 20, LND28, no LND; 42, LNDNANA16.6NANA20
Icard et al. [29]6, 50, 23, 2112NANANA3832.5NANA54
Icard et al. [34]7, 44, 24, 2412NANA30, 47, 36, 63510017NA49
Influence of surgical volume on oncologic outcome
Gratian et al. [14]NA10.5–11.2NANA243119–23NA23–2631–44
Ayala-Ramirez et al. [15]3, 37, 34, 261112, local recurrenceNA24, 6, 3.5, 0.9 yr38NANA2771
Kerkhofs et al. [18]35, stage 1–2; 14, 38NANANANA (stage 1–2), 22, 649, stages 1–3NANANANA
Hermsen et al. [22]2, 29, 34, 35NA22, R1; 69, R0NA250, without mitotaneNANA412831
Lombardi et al. [24]13, 47, 25, 158–1032–633015–244917122027

DFS = disease-free survival; FU = follow-up; LA = laparoscopic adrenalectomy; LND = lymph node dissection; NA = not available; OA = open adrenalectomy; OS = overall survival.

ENSAT stages 1–3 patients were reported by Fossa et al. [17]. A similar completeness of resection was found in 32 patients (LA: n = 17; OA: n = 15), despite the higher size and tumour stage in the OA group. Two port-site metastases were seen after LA with similar long-term oncologic outcomes (median follow-up: 29 mo; range: 11–104 mo). Also, in a single-centre study from Cleveland [19] with stages 1–4 patients (n = 44: LA: n = 18; OA: n = 26), more localised and smaller tumours were seen in the LA group. Positive resection margins were similar, and only one peritoneal carcinomatosis developed after LA. More extensive surgery with removal of adjacent organs was performed in OA, but after a median follow-up of 26 mo, the 2-yr OS and RFS did not differ significantly (39% vs 60% and 58% vs 54%, respectively). After correction for stage, a 60% risk reduction was reported in the OA group, although it was not statistically significant. Brix et al. [11] described 152 tumours ≤10 cm from a German ACC registry. No significant differences were seen between the LA group (n = 35) and matched counterparts in the OA group. In LA, significantly smaller tumours and lower stages were seen. Negative surgical margins were comparable (69% vs 55%). Also, capsule violation was equal, 8.6% versus 11.4%, for the matched OA group. Recurrence rates and death were not different. In LA, peritoneal carcinomatosis as the first recurrence occurred in one patient and in four after OA (three violations during surgery). OS and RFS were not different for completed LA (n = 23) and the matched OA group. In multivariate analysis, after correction for confounding factors like stage, similar DSS and RFS were seen.

In contrast, from the 156 patients with stages 1–3 ACC (LA: n = 46; OA: n = 110) described by Miller et al. [21], patients in the OA group had fewer positive surgical margins or spill (16% vs 30%; not significant), despite larger and higher stage tumours with more adjacent organ resections in both stage 2 and stage 3 disease. Although recurrence rate after negative surgical margins in LA was equal (69%) to OA (63%), 94% occurred in the tumour bed or peritoneum compared with 58% in OA. Even for stage 2 disease, recurrences within the tumour bed or peritoneum were seen more often after LA (55%) than OA (34%). Furthermore, the time to recurrence after stage 2 with R0 resection and after stage 3 was shorter for LA compared with OA (stage 2: 11.7 vs 29.5 mo; p < 0.002; stage 3: 4 vs 14.6 mo; p = 0.06). OS for stage 2 was in favour of OA with 51 versus 103 mo (p = 0.002), and in R0 55 versus 102 mo (p = 0.05). The authors concluded that because of a high percentage of upstaging, more positive surgical margins occurred in LA. The percentage of tumour bed recurrence or peritoneal metastases may be higher, and time to recurrence and survival may be improved by OA, even after R0 resection.

In meta-analyses of these retrospective studies, however, there were no differences in OS (pooled HR: 1.12; p = 0.65; Fig. 2B) and DFS (pooled HR: 0.83; p = 0.41, Fig. 2C) between LA and OA. Again, there was considerable heterogeneity (I2 = 44.8% and 46.8%, respectively) between studies, but no relevant publication bias on both funnel plots (Fig. 3B and 3C) and Egger tests (p = 0.36 and p = 0.82, respectively). In a sub-meta-analysis of patients who underwent potential curative resection of ENSAT stage 1 or 2 tumours [13], [17], [20], [21], and [26], there were no differences in OS (pooled HR: 0.94; 95% CI, 0.42–2.10; p = 0.87) and DFS (pooled HR: 0.85; 95% CI, 0.37–1.97; p = 0.71).

3.2. General oncologic outcome in other series

Several other retrospective studies have been published regarding oncologic outcome after ACC surgery [12], [16], [25], [27], [28], [30], [31], [32], [33], [35], and [36]. A stage-dependent improved survival for localised disease and better survival after radical surgery was shown [27], [30], [31], [32], [33], [35], and [36]. Most patients in these series were operated on with OA, and the numbers of LA were small, making comparison of outcomes difficult. However, an improved survival after OA was reported in two studies [12] and [16], and an improved OS and RFS in one after adjustment for T stage [16]. In two other studies, the increased risk for peritoneal carcinomatosis and local recurrence after LA were emphasised [25] and [28], but the numbers of LA patients were small, and many different surgeons were involved in these procedures.

3.3. Role of lymph node dissection

In an ACC registry from Germany, a specific effort was made retrospectively to compare patients with (n = 47) and without (n = 236) LND [23]. The criteria for adequate LND were a description in the surgical report that LND was performed and a minimum of five lymph nodes in the pathologic report that were found in 16.6% (n = 47) of 283 patients with stages 1–3 ACC and negative surgical margins. Median follow-up was 40 mo (LND: 59 mo; no LND: 39 mo). The LND group had larger tumours, more stage 3 (51 vs 27%; p = 0.002), and more multivisceral resections were performed (47 vs 18%; p < 0.001). All patients with LND were operated on with open surgery. There were no differences in time to recurrence and recurrence rate between patients with and without LND. In patients with histologically proven positive lymph nodes (n = 25), the time to recurrence was shorter for patients without LND (12.5 vs 31.3 mo; p = 0.002). A superior median RFS (20.4 vs 9.9 mo; p = 0.086) and DSS (>86 mo [median not reached] vs 26.2 mo; p = 0.06) was found after LND (n = 13). Although statistical significance was not reached in multivariate analysis correcting for age, stage, multivisceral resection, adjuvant treatment, and lymph node status, a reduction of risk recurrence (HR: 0.65) and disease-related death (HR: 0.54) was seen for LND patients including stage 3. In a relatively large retrospective French study [29] with stages 1–4 ACC, 32.5% of patients had an LND. The 5-yr OS was 38% (in the curative group 50%), with a better survival in localised stage, after curative surgery, age <35 yr, and no adjacent organ resections. Survival did not improve after LND in this heterogeneous group. In another, single-centre, study from France [34] in only 2 of 41 performed LNDs was microscopic invasion of lymph nodes found. Stage distribution was 52% stages 1–2 and 48% stages 3–4. Mean survival ranged from 6 to 47 mo depending on stage with an overall 5-yr survival of 35%. Between stages 2 and 3, a significant difference in 5-yr survival was found.

3.4. Influence of surgical volume on oncologic outcome

In a study from the US National Cancer Database [14], it was concluded that in HVCs, more aggressive surgical resections and adjuvant treatments are applied; however, no significant OS difference was found. An open surgical approach was chosen more often than a minimal invasive operation, and significantly fewer positive surgical margins were seen in HVCs. In another large retrospective series from MD Anderson Cancer Centre [15], it appeared that complete resection was associated with increased RFS and OS with a better outcome in specialist referral centres. After laparoscopy, higher recurrence rates were seen, although numbers of patients with a minimal invasive approach were much smaller than those treated with open surgery. In a Dutch series [18] and [22], surgery in an HVC was associated with a survival benefit for stages 1–3, although these studies had shortcomings, such as failure to correct for adjuvant therapy.

In contrast, in an Italian series [24], similar positive surgical margin rates were seen after surgery in HVCs, although fewer laparoscopic approaches were performed routinely. More aggressive surgery was done in HVCs with 22% LND compared with 7.7% in low-volume centres (LVCs), and more multiorgan resections (24% vs 8%, respectively). In addition, a higher number of patients received adjuvant therapy in HVCs. Local recurrence and distant metastases rates were higher in LVCs. The time to recurrence was shorter (25 vs 10 mo, respectively; p < 0.001). Despite this, the 5-yr OS was similar.

3.5. Discussion

In several reports from the literature, concern is expressed about peritoneal carcinomatosis and local recurrences after laparoscopy for ACC [25] and [28]. The current literature includes a number of retrospective comparative studies for localised disease after negative surgical margins [13], [20], and [26]. The LE is low (2b), but it is the best currently available literature, and in addition the groups were often matched for patient and disease characteristics. From these studies one should conclude that after LA for localised disease (all tumours ≤10 cm), time to recurrence, RFS, and OS are not different from OA. The perceived concern about peritoneal carcinomatosis is therefore not validated by these studies. It seems that as long as oncologic principles are followed, the outcome for LA is equally effective as OA, and the surgeon's technique and patient selection are the key determinants in oncologic outcome. In those studies also including patients with higher stages, several authors have described a few incidents of peritoneal carcinomatosis after laparoscopy, but RFS and OS were similar to open surgery [11], [17], and [19]. Although these studies are biased because higher stages were often operated by OA with more extensive surgery of adjacent organs, it appears evident that laparoscopy is not suitable for locally advanced disease and should only be reserved for small localised tumours. Only Miller et al. [21] described more positive surgical margins and spill after LA, despite smaller and lower stage tumours compared with open surgery. Thereafter, higher rates of recurrences in the tumour bed and peritoneum were found, although recurrence rates after negative surgical margins in LA were equal to OA. Finally, the time to recurrence for localised disease and R0 resection, and for stage 3 was shorter for LA compared with OA. OS for stage 2 was in favour of OA even in R0 resection. The authors concluded that because of a high percentage of upstaging, more positive surgical margins occurred in LA. It is evident that preoperative imaging, adequate clinical staging, and extensive surgical experience are essential for choosing the right surgical approach. The role of robot-assisted adrenalectomy is not clearly established. Postoperative results are comparable with those after laparoscopic transperitoneal resection. The approach is more comfortable for the surgeon, but a learning curve is necessary, and it is more time consuming and costly [37].

In several other series it was specifically outlined that survival after LA is worse in ACC, and the risk for peritoneal carcinomatosis and local recurrences is higher [12,16,25,28). However, in these series most patients underwent OA and only a few LA, and there was a heterogeneous surgical workforce involved. Therefore, these studies were confounded by the additional factors of surgical experience and volume of the centre.

The only conclusion that can be made concerning the role of concomitant LND is based on one study that showed a shorter time to recurrence, in patients with histologically proven positive lymph nodes, when no proper LND was performed [23]. A trend for better RFS and DSS after LND was seen. Therefore, again preoperative imaging is of utmost importance for adequate staging and treatment strategy. Whether a LND should be performed for localised disease is not clear, but in our opinion it will mainly be of diagnostic value. If concomitant LND is performed, it should be performed by open surgery, but there is no surgical standard for LND and therefore no definitive template. Thus the exact diagnostic value as well as oncologic effect (ie, the possibility that LND may be curative) cannot be assessed.

An exact definition of an HVC is not possible based on reports in the literature. The required numbers of ACC surgeries range from 4 to 10 cases per year [14] and [24] to 10 LA cases [8], or even 20 cases per year [38]. However, from several series it is evident that in HVCs more open aggressive surgical resections and adjuvant treatments were applied [14] and [24]. As a result, fewer positive surgical margins were seen, and in some studies an improved RFS and OS [15], [18], and [22]. In a Dutch series, a survival benefit was seen in referral centres [18] and [22]. In contrast, in one series similar positive surgical margins were found, but despite this, a higher local recurrence and distant metastases rate, and a shorter time to recurrence were seen in LVCs [24]. The factors that may have been influential were the more aggressive surgery and adjuvant treatment instituted in HVCs. Nevertheless, the 5-yr OS was similar.

4. Conclusions

After adequate preoperative imaging and clinical staging, LA is as effective and oncologically safe for localised ACC as OA, as long as oncologic principles are respected and the surgical margins are negative. LA should be performed by surgeons with extensive experience in laparoscopic adrenal surgery in HVCs with expertise and in multidisciplinary teams. Patients with locally advanced disease, large adrenal masses (>10 cm), and metastatic disease, for debulking purposes, should be operated on more extensively by open surgery with adequate margins. Concomitant LND could be performed to optimise staging and may contribute to prognosis in locally advanced disease. The role of LND in localised disease is not known.


Author contributions: Johan Langenhuijsen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Langenhuijsen.

Acquisition of data: Langenhuijsen, Klatte.

Analysis and interpretation of data: Langenhuijsen, Birtle, Klatte, Porpiglia, Timsit.

Drafting of the manuscript: Langenhuijsen.

Critical revision of the manuscript for important intellectual content: Langenhuijsen, Birtle, Klatte, Porpiglia, Timsit.

Statistical analysis: Klatte.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: None.

Other (specify): None.

Financial disclosures: Johan Langenhuijsen certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

Acknowledgments: The authors would like to thank Cathy Yuhong Yuan and Max Bruins for their contribution in the identification of relevant literature from the available databases.

Appendix A. Supplementary data

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Footnotes

a Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands

b Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK

c Department of Urology, Medical University of Vienna, Vienna, Austria

d Division of Urology, San Luigi Gonzaga Hospital, School of Medicine, Torino, Italy

e Department of Urology and Transplant Surgery, HEGP-Necker, APHP Université Paris Descartes, Paris, France

Corresponding author. On behalf of the YAU Renal cancer working group of the EAU. Department of Urology, Radboud University Medical Centre, Geert Grooteplein 10, 6500 HB Nijmegen, The Netherlands.

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