Keywords

13.1 Introduction

The best surgical approach for adrenocortical malignancies is still a matter of debate.

In the last 30 years, laparoscopic adrenalectomy (LA) has become the treatment of choice for benign adrenal disorders, both functioning and nonfunctioning [1]. The benefits of the minimally invasive approach are well documented in the literature and consist of improved postoperative recovery, shorter length of hospital stay, lower rate of perioperative complications and reduced cost [2, 3].

For adrenocortical carcinoma (ACC), however, the role of laparoscopy is debated, and the literature is conflicting: some observational studies raise concern regarding the oncologic outcome after a laparoscopic approach while others suggest its safety. Also, in this particular area, the literature is affected by the low incidence of the disease: no randomized trials have been published and the available studies are based on retrospective series recruited over a large time span. A curative resection should provide negative margins, integrity of the tumor capsule, en bloc removal of the tumor with the periadrenal fat and adjacent infiltrated organs, and locoregional lymphadenectomy [4]. A curative (R0) resection must be pursued whenever possible, because it is the most important determinant of long-term survival [5]. For these reasons and because of the complexity of the procedure, open adrenalectomy (OA) is the preferred approach for ACC. However, the spread of laparoscopic techniques and the evolution of the available technology, which now includes robotic assistance, allow for more extensive operations with minimally invasive techniques, keeping the debate alive.

In this chapter we analyze the available literature to identify the critical elements of the discussion. Location, tumor size and surgeon’s experience all contribute to the choice of approach.

13.2 Studies in Favor of Minimally Invasive Adrenalectomy

In a retrospective single-center study, Donatini et al. showed the association of LA with a shorter length of hospitalization without compromising long-term oncological outcomes for stage I–II ACC ≤10 cm [6]. In another retrospective single-center study, Porpiglia et al. found equal oncological outcome between patients subjected to OA and LA for stage I–II ACC when oncologic principles are respected [7]. The same conclusion is reported in a multi-institutional Italian survey by Lombardi et al. [8]. Similarly, Brix et al. described the same postoperative outcomes in OA and LA in terms of survival, capsule rupture and carcinomatosis for ACC stage I–II and even stage III, although the latter was more frequently approached with the open technique [9].

More recently, Maurice et al. used the National Cancer Database to compare outcomes for patients with stage I–IV ACC undergoing OA versus minimally invasive adrenalectomy. Although positive surgical margins were more common in the minimally invasive group, no statistically significant differences in 3-year overall survival were found between the two groups. The authors concluded that minimally invasive adrenalectomy provides acceptable long-term outcomes with faster postoperative recovery for patients with stage I–II ACC [10]. Similarly, Lee et al. retrospectively examined 201 patients from multiple centers. This study found no difference in 30-day mortality rates between the LA group and the OA group. Intraoperative tumor rupture did not occur more frequently in the minimally invasive versus open group, and R0 status was achieved in a comparable number of patients. Parameters such as T stage and not the surgical approach were found to be predictive of survival [11].

The above-mentioned papers in favor of minimally invasive adrenalectomy are summarized in Table 13.1.

Table 13.1 Studies in favor of minimally invasive adrenalectomy
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Even if these papers clearly state the safety of the LA for early ACC, a deep and critical analysis highlights methodological issues and some biases. In the papers by Donatini et al. and Brix et al., there is a major, statistically significant incidence of smaller tumors in the laparoscopic arms. Similarly, the pre-emptive exclusion of R+ cases from the analysis of data in the papers of Donatini and Lombardi may alter the interpretation. Furthermore, in the studies by Maurice and Lee, statistically significant differences were present in baseline demographics and tumor characteristics. All these anomalies may have biased the results in favor of laparoscopy.

Mpaili et al. reviewed 1171 patients staged ENSAT I–III from 13 studies and concluded that the main point of interest in this discussion is the adequacy of tumor resection rather than the surgical approach itself [12].

13.3 Studies in Favor of Open Adrenalectomy

Some supporters of OA underline the risks of laparoscopy in the management of suspected ACC related to the higher rates of peritoneal carcinosis found in their series [13]. In particular, in the study by Leboulleux et al., no other risk factor for carcinosis (e.g., dimension, stage, functional status, completeness of surgery) was identified except the type of surgical approach. Although these conclusions are likely to be limited by the—at that time—early diffusion of the laparoscopic approach, we must note that the few cases subjected to LA were mostly detected at stage I [14]. In 2018, Wu et al. published a review comprising data on 44 patients who had undergone OA or LA for stage I–II ACC with tumor size less than 10 cm. Local recurrence and peritoneal carcinomatosis trended in favor of OA but the data did not reach statistical significance. However, mean time to local recurrence and peritoneal carcinomatosis was significantly shorter in the LA group compared to the OA group [15].

Other surgeons focused on the higher rate of positive margins with the minimally invasive approach, with consequent worse prognosis and reduction of overall and disease-free survival [16]. In the largest study comparing OA versus LA for suspected ACC, published by Huynh et al. in 2016, 423 patients who had undergone OA or LA for stage I–III ACC were identified from the US National Cancer Center Database. Despite patients in the OA group having larger, more advanced tumors compared to the LA group, LA was identified as an independent risk factor for death on multivariate analysis. Furthermore, margin positivity was higher for T3 tumors treated with LA [17]. Nakanishi et al. recently reviewed 1617 cases from 11 different studies; they demonstrated a lower rate of positive resection margins in favor of OA. The open approach also had better overall and recurrence-free survival rates than laparoscopic surgery at 3 years. Unfortunately, some studies included in this review were of poor quality due to an insufficient follow-up period, so the results appear inconclusive [18].

Some authors examined how the oncological outcome can be influenced by the conversion from a minimally invasive to an open approach and by the tumor size. In a series of 588 patients by Calcatera et al., no difference in median survival was observed between LA and OA, but median survival for the minimally invasive surgery group was twice that for the converted group. Multivariate analysis then showed that size greater than 5 cm was the only predictor of conversion from LA to OA and that size greater than 5 cm, as well as positive margins, were independent predictors of worse overall survival in patients treated with laparoscopic/robotic adrenalectomy. These results appear to suggest that LA may be useful only if it is possible to achieve full resection of the ACC [19].

Finally, the role of the volume-outcome relationship was proposed for ACC by Cooper et al. In this study patients were stratified not only by type of procedure (OA versus LA) but also by location of surgery. Patients referred to the authors’ tertiary hospital after OA or LA resection at other hospitals were compared with patients treated with OA resection primarily at the authors’ hospital. A higher rate of R0 margins and a lower rate of peritoneal carcinomatosis were recorded when the OA resection was primarily performed at the tertiary hospital rather than at the referring outside hospitals. It may therefore be supposed that also the type of hospital may influence patient outcomes [20].

Table 13.2 reports the main papers in favor of open adrenalectomy.

Table 13.2 Studies in favor of open adrenalectomy
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13.4 Discussion and Guideline Recommendations

It must be underlined that a major methodological bias has affected the debate and altered the evidence. Enrollment in all these retrospective studies was conducted ex post and based on the pathological diagnosis of ACC and not on the clinical diagnosis, as it should have been. The clinical dilemma surrounding the “undetermined adrenal mass” and the difficulties encountered in the preoperative diagnosis of early-stage ACC heavily impact the conclusions of retrospective studies. In general, only a minority of early-stage ACCs are correctly recognized and staged before surgery; more often the diagnosis is formulated postoperatively by the pathologist. In the co-operative Italian paper, 53% of ACCs were approached with a preoperative diagnosis of incidentaloma (83% in the laparoscopic arm) [8]. The penetration of this phenomenon varies greatly in the different papers and its real impact cannot be recognized owing to the retrospective nature of the studies. Indeed, this is a major bias in the interpretation of data: oncologic outcomes of different surgical techniques are compared across inhomogeneous technical settings with a significant percentage of surgical procedures performed for lesions which are not diagnosed as malignant and, it is reasonable to assume, are not approached with those cautions and technical requirements normally adopted when approaching a malignant lesion. Inevitably, considering the “grey scale” characteristic of the undetermined adrenal mass, those masses that appear at higher risk of malignancy (larger tumors, enlarged lymph nodes, inconclusive imaging) seem to be more often approached with open surgery while those presenting more favorable characteristics are more likely to be treated with minimally invasive techniques.

The above considerations justify the prudential use of the laparoscopic approach suggested by all the guidelines [4, 21,22,23]. The open approach as the surgical standard of care for confirmed or highly suspected ACC is recommended by: the European Society of Endocrine Surgeons (ESES), European Network for the Study of Adrenal Tumors (ENSAT), European Society for Medical Oncology (ESMO), European Reference Network on Rare Adult Cancers (EURACAN), American Association of Clinical Endocrinologists (AACE), American Association of Endocrine Surgeons (AAES), and Society of Gastrointestinal and Endoscopic Surgeons (SAGES). Furthermore, they suggest the use of the laparoscopic approach only in the absence of local invasion, suspected metastatic lymph nodes and when the principles of oncological surgery can be respected. This surgery should be reserved for expert surgeons and centralized to high-volume institutions. In any case, immediate conversion to open surgery whenever there is a risk of incomplete resection if the operation is conducted laparoscopically is strongly recommended.