Future ONCOLOGY
Minimally invasive adrenal surgery: virtue or vice?
Jared S Winoker1, David T Ahlborn1, Olamide O Omidele1, Gustavo Fernandez-Ranvier2, Ithaar H Derweesh3 & Reza Mehrazin*,1
1 Department of Urology and Oncological Science, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY 10029-6574, USA
2 Department of Surgery, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY 10029, USA
3 Department of Urology, UC San Diego Health System, 200 W Arbor Drive, San Diego, CA 92103-8897, USA
* Author for correspondence: Tel .: +1 212 241 4812; Fax: +1 212 987 4675; reza.mehrazin@mountsinai.org
Adrenocortical carcinoma (ACC) is a rare malignancy associated with poor prognosis despite available treatments. In patients with localized or locally advanced disease, complete resection with negative mar- gins offers the only potential for cure. Unfortunately, most patients develop local and distant recurrence following initial resection highlighting the importance of meticulous surgical technique in the hands of an experienced surgeon. While minimally invasive surgery (MIS) has supplanted open surgery for small to medium-sized benign adrenal tumors, controversy surrounds the use of MIS for resection of ACC. We sought to provide an overview of the key oncological principles in the surgical management of ACC and to critically review the literature comparing outcomes between the open and MIS approaches.
First draft submitted: 23 August 2017; Accepted for publication: 9 November 2017; Published online: 18 January 2018
Keywords: adrenal . adrenal cancer . adrenalectomy . adrenocortical carcinoma . laparoscopic adrenalectomy . minimally invasive surgery
Adrenocortical carcinoma (ACC) is a rare malignancy with an extremely poor prognosis [1-3]. It is estimated that ACC is present in one to two cases per million individuals, and the reported 5-year survival rate ranges between 30 and 50% [4,5]. Notwithstanding, metastatic ACC has a median survival of <1 year [6]. Unfortunately, the majority of patients have locally advanced or metastatic disease at diagnosis and a poor disease-specific survival. For those with localized or locally advanced disease, aggressive surgical resection with negative margins remains the only chance for potential long-term cure.
Historically, open adrenalectomy (OA) had been the gold standard for the surgical management of benign adrenal tumors. More recently, however, the use of minimally invasive surgery (MIS) has gained popularity due to its lower associated complications rate, shorter postoperative length of stay and reduced pain for the patient [7]. While MIS techniques, including laparoscopic adrenalectomy (LA) and robotic adrenalectomy (RA), have largely supplanted open surgery as the standard treatment for small to medium-sized (≤6 cm) benign tumors, controversy exists with respect to their role in the treatment of ACC [8]. Much of this uncertainty stems from the contradictory conclusions of a limited number of retrospective studies, in conjunction with the highly aggressive nature of the disease. For example, it is estimated that >50% of patients with ACC who have had an R0 resection will develop a local recurrence [9,10]. Thus, the oncologic efficacy of MIS for ACC, which may be limited in its ability to offer a wide resection with minimal manipulation of the tumor, remains in question. This article provides an overview of the key oncological principles in the surgical management of ACC and critically evaluates the existing evidence in favor of and against an MIS approach.
Methods
We performed a systematic search of the medical literature using the PubMed and Medline electronic databases to identify all relevant studies using the following keywords: adrenocortical carcinoma, adrenal cancer, adrenalectomy, laparoscopic adrenalectomy, minimally invasive and open adrenalectomy. Comparative studies evaluating minimally invasive and open surgical management of ACC were considered for inclusion. Duplication of data in multiple
Future Medicine
publications from the same authors were excluded, as were editorials, comments, case reports and studies including less than five patients treated with a minimally invasive approach.
Technical aspects of ACC surgery: surgical approach & oncological principles Complete resection
There is a general agreement that complete locoregional excision, as initial management of ACC, provides the only potential for cure and best overall prognosis. In a retrospective analysis of patients with ACC from the Memorial Sloan-Kettering Cancer Center, Schulick and Brennan reported the outcomes of 113 patients, 107 of whom underwent at least one surgical resection for ACC. The majority (55%) of patients had functional lesions and median tumor size was 14 cm. Overall survival at 5 years was 37% with median survival of 38 months. After stratifying by completeness of resection, complete primary resection had a median survival of 74 months while incomplete primary resection had a median survival of 12 months (p < 0.001). Although the influence of resection status on patient outcomes was not stratified by disease stage, introducing potential selection bias, the efficacy of maximal resection was further demonstrated by the outcomes of patients undergoing repeat resection. In total, 83 patients underwent repeat resection for local and/or distant recurrences. In those cases in which an R0 resection was performed, median survival was 74 months, as compared with 16 months for those with incomplete resection [9].
Similarly, a retrospective review of the Norwegian cancer registry from 1970 to 1984 found no difference in survival between debulking surgery and no surgical intervention, further highlighting the importance of maximal resection for ACC [11].
More recent retrospective studies have confirmed the findings of Schulick and Brennan [4,12-14]. These studies are generally based on national databases and confounded by the introduction of adjuvant and neoadjuvant therapies. Despite these additional treatments, the observed survival benefit of complete resection persists. In a 2008 review of the National Cancer Database, Bilimoria et al. identified 3982 patients diagnosed with ACC from 1985 to 2005. Of those, 57.4% underwent surgery alone and an additional 16.0% underwent surgery with adjuvant therapy. Margins were reported in 2117 patients, with 19.4% having positive margins. Positive surgical margins came with a higher risk of death with a hazard rate (HR) of 2.06 (95% CI: 1.74-2.43; p < 0.0001). On multivariable analysis, nodal metastases, distant metastases and poor tumor differentiation were associated with a higher likelihood of margin-positive resection [6].
Resection of adjacent organs
With respect to surrounding structures, vascular involvement - renal vein, adrenal vein, inferior vena cava - is not an uncommon finding in ACC with some series reporting incidences as high as 24.8% [15,16]. By contrast, direct invasion into adjacent organs is less common with a reported rate of 12% [17]. Given the importance of complete resection and the fact that the adrenal gland and kidney share the same anatomical space, surgeons have explored the concept of en bloc resection of the adrenal tumor with its ipsilateral kidney, as well as other adjacent organs. Icard et al. investigated the utility of this practice in the early 1990s [18]. At the time, they advocated for en bloc removal of the ipsilateral kidney and other nearby structures to allow for wide operative margins, removal of nearby renal hilar lymph nodes and minimal risk of surgical tumor violation. In their published data, 32% of 48 patients over a 12-year period underwent extensive resections, including one partial pancreatectomy, four nephrectomies, three right hepatectomies and three intestinal resections, all for apparent invasion. Additionally, 11 patients underwent en bloc nephrectomy without obvious tumor invasion. While there were no observed benefits in outcomes, the authors did theorize that by taking out the adjacent kidney, they were better able to achieve negative margins and therefore improve survival. A review of the Italian National Registry for ACC also failed to find a survival advantage for concurrent nephrectomy with adrenalectomy in cases without evidence of direct tumor invasion [19]. Not surprisingly, there exist no head-to-head studies that have investigated concurrent adjacent organ resection and there are no studies that have convincingly demonstrated a benefit of such practice. In the absence of consensus guidelines, the oncological principle of complete resection with wide margins should guide surgeons as to whether or not it is prudent to remove an adjacent organ on a case-by-case basis, taking into account preoperative radiographic studies and gross inspection during surgery.
Lymph node dissection
Another area of contention is the role or definition of routine lymph node dissection (LND) in the management of ACC. Local recurrence is a common occurrence, affecting up to 85% of patients following radical resection [20].
Moreover, lymph node involvement (LNI) is estimated to occur in approximately 20% of ACC cases [21]. In 2015, a review of the National Cancer Institute database analyzed the potential associations between LND, LNI and cancer-specific death (CSD). The study found disease stage to be the most significant determinant of whether or not an LND was performed and LNI was strongest predictor of CSD. Performing LND was also found to be a significant predictor of CSD, though this was likely an artifact of selection bias. No comparative analyses were performed to assess whether or not LND conferred a survival advantage in patients of similar stage and resection status [22]. In an analysis of the Surveillance, Epidemiology, and End Results (SEER) database, one group found no disease-specific survival advantage in patients who underwent LND regardless of tumor size or staging (p =0.30) [23].
While lymph node status is a widely accepted predictor of disease recurrence and less favorable outcomes, lymphadenectomy is infrequently performed [21]. Several groups advocate its routine use in primary surgical treatment [24,25], while others reserve excision for cases of macroscopic invasion of regional nodes and surrounding structures [26]. On evaluating patterns of recurrence, recent evidence points to a high rate of LNI in the locoregional para-aortic, paracaval and ipsilateral renal hilar regions. Based on these findings, the authors recommended extended initial LND including the aforementioned node packets regardless of gross appearance of nodes [20]. Despite the purported potential for improved staging leading to more favorable oncological outcomes, clinical evidence for routine LND is still lacking.
Tumor handling
Taking care to remove the tumor and surrounding tissues en bloc without grabbing or touching the tumor is one of the tenets of an oncologically sound resection. As with other cancers, ACC has the potential for gross or microscopic invasion of the tumor capsule. Apparent violation of the tumor capsule or affected gland is an important prognostic factor and even microscopic abrasions during the course of surgery can result in spillage and shedding of malignant cells [17,27]. In fact, the University of Michigan group point to this as the major reason why laparoscopic resections have worse outcomes, due to inadvertent microabrasion of the tumor with laparoscopic tools [28]. Leboulleux et al. suggest movement of peritoneal fluid secondary to insufflation during laparoscopy may promote tumor cell dissemination portending a greater risk of peritoneal carcinomatosis (PC) [29].
Minimally invasive surgery versus open adrenalectomy for ACC Consensus statements
In 2003, the first International Adrenal Cancer Symposium convened to compare treatment regimens for ACC with the goal of defining standards of surgical care for this aggressive disease. The group concluded that there was no role for LA in the resection of a known or likely ACC. However, controversy regarding the surgical management of indeterminate lesions persisted [30]. More recently, several national societies such as the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons have released formal recommendations advocating the use of open resection by an experienced surgeon [31]. These recommendations are based on the fact that LA for the treatment of ACC has not yet been fully studied and OA represents a better option due to its oncologic efficacy and acceptable risk profile. With that being said, there is still debate surrounding the utility of LA for both masses of indeterminate malignant potential and known ACC lesions of relatively small size. Contemporary guidelines from two prominent European medical associations endorse LA as an acceptable option for stage 1 and 2 tumors <10 cm in diameter if wide resection is performed to attain negative surgical margins [8,32]. Unfortunately, neither of these guidelines addresses the risk of preoperatively unidentified stage 3 disease or the reality that positive margins may occur despite intentions to perform an R0 resection.
Critical review of the evidence
To date, there are limited data evaluating the oncological efficacy of LA versus OA for the surgical management of ACC (Table 1). The ability to draw concrete conclusions from these studies is hampered by elements of study design and multiple confounding factors. For one, all of the published studies are retrospective in nature with relatively few cases for analysis, owing to the rarity of ACC and advanced stage at which the disease is often diagnosed. Referral bias is another pervasive concern among the available literature. Many patients included in these published analyses received their initial surgical treatment at a low-volume center and were subsequently referred to a tertiary care center, further confounding potential relationships between surgical approach and oncologic outcomes.
| Table 1. Comparative studies evaluating laparoscopic adrenalectomy versus open adrenalectomy for the surgical | ||||||||
|---|---|---|---|---|---|---|---|---|
| management of adrenocortical carcinoma. | ||||||||
| Study (year) | Number of patients | Median follow-up | Positive margins, n (%) | Overall recurrence, n | Local recurrence, n | Peritoneal carcinomatosis, | Median time to recurrence | Ref. |
| (months) | (%) | (%) | n (%) | (months) | ||||
| Gonzalez et al. (2005) | LA 6 | 28 | N/A | 100% | 50% | 83% | N/A | [33] |
| OA 133 | 86% | 38% | 13% | 13 | ||||
| Cooper et al. | LA 46 | 34.4 | 28.3% | 76.1% | N/A | 54.3% | 10.9 | [34] |
| (2013) | OA 210 | 17.6% | 87.3% | 27.6% | 9.5 | |||
| OA' 46 | 8.7% | 58.7% | 19.6% | 19.6 | ||||
| Leboulleux et al. (2010) | LA 6 | 35 | 17% | N/A | 34% | 67% | Overall: 201 | [29] |
| OA 58 | 36% | 72% | 27% | |||||
| Porpiglia et al. (2010) | LA 18 | 35 | N/A | 50% | 33% | 0% | 23 | [35] |
| OA 25 | 64% | 24% | 0% | 18 | ||||
| Brix et al. (2010) | LA 35 | 39.3 | 31.4% | 77% | N/A | 3% | 24.2 | [36] |
| OA 117 | 40% | 69% | 3% | 21.5" | ||||
| Lombardi et al. (2012) | LA 30 | 42 | 0 | 27% | 13% | N/A | 29 | [37] |
| OA 127 | 0 | 38% | 11% | 27 mean | ||||
| Miller et al. (2010) | LA 17 | 36.5 | 50% | 63% | 25% | 18% | 9.6 mean | [38] |
| OA 71 | 18% | 65% | 20% | 11% | 19.2 | |||
| Mir et al. (2013) | LA 18 | 26 | 39% | 22% | 55.6% | 5.5% | 9.7 | [39] |
| OA 26 | 38% | 27% | 46.2% | 0% | 13.8 mean | |||
| Fosså et al. (2013) | LA 17 | 29.1" | 29.4% | 71% | 5.9% | 11.8% | N/A | [40] |
| OA 15 | 20.0% | 100% | 6.7% | 0% | ||||
| Donatini et al. | LA 13 | 66 | 0% | 31% | N/A | N/A | N/A | [41] |
| (2014) | OA 21 | 0% | 24% | |||||
OA cases performed at outside facility.
OA cases performed at index facility.
Three cases (all OA) had PC at diagnosis.
“Reflects time to development of PC.
Matched pairs analysis.
ttMedian follow-up for 12 of 32 patients still alive at time of review.
LA: Laparoscopic adrenalectomy; N/A: Not available; OA: Open adrenalectomy; PC: Peritoneal carcinomatosis.
In a retrospective study from MD Anderson Cancer Center, Gonzalez et al. investigated recurrence and survival in 139 patients (133 OA; 6 LA) who underwent adrenalectomy for ACC [33]. At a median follow-up of 28 months, the overall recurrence rates for patients undergoing OA and LA were 86% (115/133) and 100% (6/6), respectively. Of note, all six LA patients underwent initial surgery at lower volume-referring centers and were subsequently referred to the index institution, likely for management of recurrent disease. The authors reported a difference in the pattern of failure between the two groups. Patients undergoing an MIS approach had a very high incidence of PC as an initial site of recurrence (83%), as compared with those who underwent OA (8%; p = 0.0001). These findings could be accounted for, in part, by technical error; one of the six patients had fracture of the tumor during attempted specimen extraction and another patient was converted to open due to uncontrolled intraoperative bleeding, possibly increasing the risk for surgical seeding.
In a follow-up report from the same institution, Cooper et al. reported the long-term oncologic outcomes of 302 patients, 46 of whom underwent LA [34]. Despite significantly smaller tumors with a trend toward lower stage of disease, the authors found an increased risk of PC in the LA cohort, similar to the findings of the previous study. Additionally, the use of open surgery was independently associated with improved recurrence-free and overall survival after controlling for T stage (p < 0.0001). The clinical significance of recurrence by PC was highlighted by the fact that a mere 15.2% of these patients, versus approximately 36% of patients with any type of recurrence, were amenable to salvage resection (p = 0.0004). It has been established that complete resection of all disease in patients with recurrence is associated with higher rates of survival [9].
Leboulleux et al. performed a retrospective review of 64 patients (OA 58; LA 6) with the primary focus of investigating the relationship between surgical approach and the development of peritoneal recurrence [29]. Similar to findings of several other studies, the MIS approach was associated with a significantly higher rate of PC (LA: 67% vs OA: 27%; p = 0.016) [33,34]. Among the four LA patients with PC, three received an R0 resection with negative surgical margins. Moreover, the use of MIS was the only identified risk factor for the development of PC; neither tumor size, tumor stage, nor completeness of surgical resection were associated.
In 2010, Miller et al. reported the outcomes of 88 patients from the University of Michigan. In total, nearly 80% of all surgical resections and all 17 LA procedures were performed at an outside center prior to referral [38]. Median tumor sizes in LA and OA patients were 7.0 cm (range: 4-14) and 12.3 cm (range: 5-27), respectively. Despite similar overall recurrence rates between the two groups (LA: 63% vs OA: 65%; p = 0.22), patients who underwent LA were more likely to have documented intraoperative tumor violation or positive surgical margins (LA: 50% vs OA: 18%; p < 0.01) and experienced shorter time to recurrence (LA: 9.6 vs OA: 19.2 months; p < 0.005). These findings were persistent even when examining tumors <6 cm, a size many surgeons would presume easier to resect and therefore amenable to an MIS approach [42]. Interestingly, a significantly greater number of patients who underwent OA developed distant metastases (LA: 24% vs OA: 49%; p = 0.03). Tumor biology is an important consideration in evaluating the risk for local or distant recurrence [43]. Seventy percent of patients in the LA cohort had localized disease (stage I/II) as compared with 51% of those in OA cohort.
In 2012, an extended follow-up study from the same authors confirmed the previous conclusion that LA is inferior to OA for the management of ACC [28]. The study evaluated 156 patients with stage I-III ACC and 26.5 months median follow-up - 46 and 110 patients underwent LA and OA, respectively. Despite larger tumors and a greater percentage of stage III disease, patients who underwent OA had a lower rate of positive surgical margins or tumor spillage (LA: 30% vs OA: 16%; p = 0.04). Stratifying by tumor stage, patients with stage II disease who underwent LA had shorter time to local or peritoneal recurrence and shorter overall survival. With respect to overall survival and time to recurrence (local and/or distant), the inferiority of LA versus OA was preserved even when comparing only those patients who underwent R0 resections. Of note, the use of adjuvant mitotane (p = 0.15) or external beam radiation therapy (p = 0.16) in margin-negative patients.
Lombardi et al. reported the results of a large multi-institutional Italian survey, comparing the oncologic outcome of MIS and OA in 156 patients with stage I and II ACC who underwent an R0 resection [37]. Thirty patients underwent resection by MIS approach; 126 had open surgery. There were no significant differences noted between the OA and MIS groups with respect to local recurrence rate (LA: 21% vs OA: 19%; p = 0.497), 5-year disease-free survival (LA: 58.2% vs OA: 38.3%) or mean time to recurrence (LA: 29 ± 33 months vs OA: 27 ± 27 months; p = 0.839). This was also true for 5-year overall survival rate (LA: 66.5% vs OA: 47.5%; p = 0.2). On the basis of their findings, the authors suggested that an MIS approach is not inferior to standard OA in terms of oncologic efficacy for the treatment of clinically localized ACC. However, such conclusions are based on retrospective exclusion of all patients with locally advanced disease and those with a positive surgical margin following resection. Furthermore, the rate of postoperative upstaging is not reported. It must be appreciated that these exclusions represent two not insignificant assumptions that may limit generalizability of the findings. It is well established that preoperative tumor stage and completeness of resection by an experienced surgeon are two of the major determinants of long-term survival in this patient population [44].
In a study involving 43 ACC patients (18 of whom underwent LA), Porpiglia et al. reported evidence that LA may be comparable to OA with respect to recurrence-free survival in patients with stage I or II disease when the principles of surgical oncology are upheld [35]. The median follow-up duration for all patients was 35 months (range: 11-72 months). Specifically, the median recurrence-free survival for LA and OA was 23 and 18 months, respectively (p = 0.8), and surgical approach was not an independent risk factor for disease recurrence on multivariate analysis (p = 0.3). Rate of any recurrence (LA: 50% vs OA: 64%) and pattern of recurrence were similar for both groups, as well. Although not clearly defined, local recurrence was 33.3% for the LA group and 24% for the open group. The external validity of this study is, however, limited by several important exclusion criteria. The analyses excluded patients with positive surgical margins, tumor capsule violation, conversion to an open procedure, postoperative upstaging to stage III disease or those who did not undergo radical resections. This is important as these factors represent the challenging elements of an oncologically sound resection and are integral considerations in the decision to pursue a laparoscopic approach. Their absence from the analysis hinders the ability to evaluate the oncological equivalence of the two techniques.
In one of the larger studies to date, authors representing the German ACC Registry Group compared the oncologic results of 152 patients who underwent LA or OA for the treatment of stage I-III ACC with a tumor diameter ≤10 cm [36]. Using both matched pairs and multivariate analyses, the authors reported similar disease- specific and disease-free survivals for the two surgical approaches - HR for death versus recurrence of 0.79 (95% CI: 0.36-1.72; p = 0.55) and 1.07 (95% CI: 0.61-1.87; p = 0.82), respectively. Similar findings were demonstrated on multivariate analysis ([HR for death: 0.98; 95% CI: 0.50-1.92; p = 0.96]; [HR for recurrence: 0.91; 95% CI: 0.56-1.47; p = 0.69]). There were no reported differences in frequency of PC (LA: 3% vs OA: 3%; p-value
not significant) or tumor capsule violation (matched pairs analysis, LA: 8.6 vs OA: 11.4%), but disease stage was unknown for these occurrences. Based on the aforementioned findings, the authors concluded that the oncological outcomes after LA and OA are comparable when performed by an experienced surgeon on patients with clinically localized ACC of limited size. However, the study is not without limitations. Similar to other publications, the LA cohort was characterized by smaller median tumor size (LA: 6.2 cm vs OA: 8 cm; p < 0.001). Furthermore, nearly three-times as many patients undergoing OA had stage III disease (LA: 11.4% vs OA 32.5%; p < 0.001) as LA would likely not be considered for patients with preoperatively identified locally advanced disease. This potential bias toward more aggressive disease in the OA group could confound the apparent noninferiority of an MIS approach. With respect to surgical margins, despite comparable positive margin rates after OA and LA, resection status was unknown in 37% of patients (LA: 26% vs OA: 33%).
Looking at 44 patients with ACC treated at a single center (LA: 18 vs OA: 26), Mir et al. found OA was associated with a relative risk reduction in both recurrence and mortality [39]. The 2-year recurrence-free and overall survivals for OA versus LA were 54 vs 58% (p = 0.6) and 60 vs 39% (p = 0.7), respectively. These differences were not statistically significant, though the authors attributed that to the relative rarity of the disease and the small number of patients available for analysis. While many other studies included only patients with localized stage I or II disease, Mir et al. incorporated outcomes for all stages of disease. This may have reduced potential bias in their results, better reflecting the aggressive nature of ACC and its more common presentation - locally advanced or metastatic at the time of diagnosis. In this series, >60% of patients had a tumor >10 cm in diameter and only 13% had a tumor <5 cm at presentation. Not surprisingly, patients who underwent LA had smaller median size of tumors (LA: 7 cm vs OA: 13 cm; p = 0.001) and lower clinical stage at diagnosis (LA: 18% vs OA: 65% cT3-4; p = 0.001). In addition to small numbers and retrospective design, the study was further limited by the inconsistency with which LND was performed and the unknown percentage of surgeries complicated by tumor capsule violation.
In 2013, Fosså et al. performed a single-center retrospective comparison of all patients with stage I-III tumors who underwent surgery [40]. LA was performed in 17 patients; OA was performed in 15 patients. The authors demonstrated comparable oncologic outcomes between the groups, though LA was associated with more favorable postoperative outcomes than OA. The rate of margin-positive resection in patients who underwent LA was 29.4%, as compared with 20.0% for those who underwent OA (p = 1.0). Overall recurrence rates were 71% (12/17) for LA versus 100% (15/15) for OA and there was no significant difference time to recurrence or pattern of relapse (p = 0.33). Further, the authors found no differences in rate of capsule violation and/or tumor spillage (LA: 29.4% vs OA: 13.3%). With respect to intraoperative and postoperative outcomes, LA was associated with fewer and less severe intraoperative incidents, shorter operative time, less blood loss and shorter hospital stay. However, it is worth noting that patients in the LA group had significantly smaller tumor sizes and trended toward lower stage disease and better performance status.
Most recently, Donatini et al. reported the results of a large multi-institutional review comparing the oncologic outcomes of LA (n = 13) versus OA (n = 21) for patients with stage I/II ACC and a tumor diameter <10 cm who underwent resection with negative margins [41]. The authors found no differences between the groups with respect to disease-specific (p = 0.65), disease-free (p = 0.96) or overall survival (p = 0.634) at a median follow-up of 66 months. In the LA group, 31% of patients recurred, as compared with 24% in the OA group (p = 0.655). There was only one reported occurrence of tumor capsule rupture (patient in the OA group) and there were no LA conversions to open approach, likely reflecting the stringent inclusion criteria. Similar to other reviews, the authors concluded that an MIS approach is an acceptable alternative with comparable outcomes to OA when performed at an expert referral center using meticulous, oncologically sound surgical technique in carefully selected patients - specifically, individuals with clinically localized disease and a tumor diameter <10 cm. As previously mentioned with regards to other studies, such inclusion criteria are quite restrictive and may not accurately reflect the majority of real-world cases. In reality, microscopic T3 disease can be missed preoperatively and therefore the exclusion of such locally advanced cases after the fact introduces significant bias and limits the external validity of the findings.
Limitations
On review of the available literature, the findings are conflicting and the few comparative studies that exist are imbued with methodological flaws. In general, the reviewed studies report on a relatively small number of patients, particularly those treated with LA. The studies are also limited by a lack of randomization introducing the risk for selection bias. It is also worth noting that many of the LA patients evaluated were referred to the reporting
Records identified through electronic search (n = 2831)
Records not considered based on title and/or abstract (n = 2804)
Full-text articles assessed for eligibility (n = 27)
Articles excluded (n = 17)
Studies included in qualitative synthesis (n = 10)
institutions either for treatment of disease recurrence or for high risk of recurrence. It is therefore unknown whether or not the findings of these studies were confounded by differences in individual surgeon experience or technique, as opposed to the surgical approach itself.
In those studies that found no significant difference in outcomes for LA and OA, there was a trend of smaller tumors and lower stage disease. Several of the studies excluded patients with greater than T2 disease, whether identified pre-, intra- or postoperatively. It is often difficult to determine microscopic T3 disease. By excluding such nonlocalized cases retrospectively, the series of patients are purged of what are likely to be more biologically aggressive cases with higher risk for recurrence and PC. Further, the use of such strict inclusion criteria may not accurately reflect the aggressive, real-world nature of ACC as most patients present with locally advanced or metastatic disease. Support for an MIS approach was predicated on meticulous surgical technique at a high- volume institution. Unfortunately, variable access to care, including economic disparities and long travel distances, may preclude many patients from referral to such specialized centers [45]. Despite the recent reports that suggest comparable risks of local recurrence and PC between the two approaches, most of the other results are equivocal, inconclusive or inferior in outcome in patients treated with LA.
Conclusion
ACC is a highly lethal malignancy that warrants complete, meticulous resection, and outcomes are likely to be unfavorable if the principles of an oncologic surgery are not respected, regardless of surgical approach. To date, there are limited data comparing outcomes between OA and LA for the management of ACC. The few retrospective and meta-analytic studies that exist are hampered by limitations and largely contradictory, lacking incontrovertible evidence of oncologic equivalence between the two approaches. While several authors have advocated the use of LA for smaller, localized tumors, concern has been raised regarding the ability to achieve consistent oncological resection by an MIS approach as compared with open surgery. Based on the findings of this review, a more conservative approach by open resection is recommended for ACC lesions as well as for larger adrenal tumors of indeterminate malignant potential.
Future perspective
Although excellent outcomes for adrenal surgery are often feasible with utilization of an MIS approach, based on available literature, its efficacy for resection of ACC and larger, malignant adrenal tumors is questionable. This controversy could possibly be resolved by well-designed randomized controlled studies. For now, a multidisciplinary approach with centralization of ACC care to higher volume, tertiary centers is needed to optimize patient outcomes.
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Executive summary
· Adrenocortical carcinoma (ACC) is a rare and aggressive neoplasm.
· Complete resection with negative surgical margins is of the utmost importance and one of the most powerful prognostic factors. Surgery may require multivisceral resection, vascular resection or locoregional lymphadenectomy.
· Regional lymph node dissection provides improved staging information and may be advisable based on an observed negative association between lymph node involvement and patient outcomes. However, routine practice and extent of dissection remain controversial as there has yet to be any proven survival benefit.
. Local recurrence and distant metastasis are frequent following initial resection and associated with poor prognosis. This highlights the importance of meticulous operative technique and adherence to oncologic principles regardless of surgical approach.
· Classically, open adrenalectomy has been the standard treatment for ACC, particularly for larger tumors and those featuring invasion of adjacent structures.
· Owing to flawed, retrospective studies and relative rarity of the disease, controversy surrounds the use of minimally invasive surgery (MIS) and its oncologic efficacy in ACC.
. While select, high-volume centers advocate MIS as an equally effective alternative to open surgery, many of the reported oncologic outcomes for patients undergoing MIS are equivocal, inconclusive or inferior to those treated with open adrenalectomy.
· Larger, well-designed studies are needed to better elucidate the relative oncologic efficacies of the two approaches.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan- cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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Review Winoker, Ahlborn, Omidele, Fernandez-Ranvier, Derweesh & Mehrazin
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