€ URRENT PINION
What is the appropriate role of minimally invasive vs. open surgery for small adrenocortical cancers?
Rocco Bellantone, Celestino P. Lombardi, and Marco Raffaelli
Purpose of review
The role of endoscopic adrenalectomy for adrenocortical carcinoma is the most controversial and debated points in adrenal surgery. We reviewed the most recent literature on this topic.
Recent findings
From the amount of available data (even if not conclusive), the following could be extrapolated: first, for patients with apparently localized disease the adrenal gland should be removed en bloc with the entire retroperitoneal fat pad, which also includes some periadrenal lymph nodes, but no extended resection is necessary in absence of involvement of adjacent structures; second, in experienced centers, oncologic outcome for endoscopic adrenalectomy is not inferior to open adrenalectomy when strict selection criteria and the principles of oncologic surgery are respected. When performed by nonexperienced surgeons, endoscopic adrenalectomy may be associated with a higher rate of positive margin and local recurrence; third, patients observed at specialized referral centers receive a more accurate preoperative workup that allows a better operative planning and a more comprehensive postoperative treatment.
Summary
Although waiting for further more exhaustive studies, we think that for suspected adrenocortical carcinoma, smaller than 8-10 cm and without pre or intraoperative evidence of local invasion, endoscopic adrenalectomy in a referral center seems to be an acceptable option.
Keywords
adrenocortical carcinoma, endoscopic adrenalectomy, laparoscopic adrenalectomy, open adrenalectomy
INTRODUCTION
Endoscopic adrenalectomy is the gold standard treatment for small to medium-sized (≤6cm) benign adrenal tumors [1-3]. Conversely, the role of endoscopic adrenalectomy for malignancies is still controversial [4,5].
Open adrenalectomy is the procedure of choice for invasive adrenocortical carcinoma (ACC) [5-11]. The growing experience with endoscopic adrenalectomy has led some authors to propose it also for large and potentially malignant adrenal tumors [12]. Moreover, with the widespread diffu- sion of endoscopic adrenalectomy, the number of patients with adrenal incidentaloma referred to adrenalectomy increased [13]. This implies increased risk of unexpected pathological diagnosis of ACC after endoscopic adrenalectomy [14]. Indeed, ACC is frequent up to 10% in patients operated for adrenal incidentaloma [15]. In the absence of radiological evidence of invasion of surrounding tissues, lymph node involvement, intravenous thrombus or distant metastases, it
may be difficult to predict malignancy in adrenal incidentaloma [15].
Surgery is of utmost importance in the treat- ment of localized ACC (European Network for Study of Adrenal Tumors - ENSAT- stage I-III) [16] because a margin-free resection provides the only means to achieve long-term cure [10,17]. Some reports demonstrated an increased risk of positive margin or tumor spill [14], peritoneal carcinomato- sis [18,19] and earlier recurrence [14] in patients undergoing endoscopic adrenalectomy for localized ACC. Similar findings have led an international
Division of Endocrine and Metabolic Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
Correspondence to Professor Marco Raffaelli, U.O. di Chirurgia Endo- crina e Metabolica, Istituto di Semeiotica Chirurgica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, L.go A. Gemelli 8, 00168 Rome, Italy. Tel: +39 06 30154199; fax: +39 06 30156086; e-mail: marco raffaelli@rm.unicatt.it
Curr Opin Oncol 2015, 27:44-49
DOI:10.1097/CCO.0000000000000144
KEY POINTS
· Margin-free (RO) resection in patients with ACC is the only means to achieve long-term cure.
. In the absence of invasion of adjacent structures, the adrenal gland should be removed en bloc with the entire retroperitoneal fat pad, respecting the rule of oncologic surgery (avoid any tumor grasping or fracture).
· Data concerning oncologic results of endoscopic adrenalectomy vs. open adrenalectomy in patients with localized ACC are not conclusive.
· In experienced centers, oncologic outcome of endoscopic adrenalectomy for localized ACC seems not inferior to open adrenalectomy, whilst when performed by nonexperienced surgeons, endoscopic adrenalectomy may be associated with a higher rate of positive margin and local recurrence.
. For suspected ACC, smaller than 8-10 cm and without pre or intraoperative evidence of local invasion, endoscopic adrenalectomy in a referral center seems to be an acceptable option.
consensus conference to strongly discourage endo- scopic adrenalectomy for the treatment of known or suspicious ACC [20]. On the contrary, recently pub- lished comparative studies based on single center [21] or multiinstitutional series [22] showed that the oncologic outcomes of localized ACC following endoscopic adrenalectomy could be similar to those seen after open adrenalectomy.
As a consequence, the role of endoscopic adre- nalectomy in the treatment of ACC has emerged as one of the most controversial and debated points in adrenal surgery.
The controversy is reflected even in the published guidelines. Indeed, the Society of American Gastro- intestinal and Endoscopic Surgeons strongly recommend open adrenalectomy for patients with suspected ACC [23], whereas the European Society of Endocrine Surgeons stated that endoscopic adre- nalectomy for’ .. . ACC/potentially malignant tumors … may be performed for pre and intraoperative stage 1-2 ACC and tumors with diameter <10 cm’ [24]. Similarly, the guidelines of the European Society of Medical Oncology consider endoscopic adrenalec- tomy ‘a safe and effective procedure for … a selected group of patients with small ACCs (<8 cm) without preoperative evidence of invasiveness’ [25].
This article will briefly review the most recent literature on this topic, including all the original articles focusing on the surgical approach to small, localized ACC published between December 2012 and July 2014.
1040-8746 @ 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
ENDOSCOPIC VS. OPEN ADRENALECTOMY FOR ADRENOCORTICAL CARCINOMA
When assessing the role of endoscopic adrenalec- tomy in patients with ACC, in our opinion three main questions should be answered. First, which should be the optimal extension of primary resec- tion for patients with ACC? Second, is the oncologic outcome different in endoscopic adrenalectomy vs. open adrenalectomy? Third, where should patients be referred for adrenalectomy for suspected ACC?
Optimal extension of primary resection in patients with localized adrenocortical carcinoma
Although the decision to operate patients with stage IV disease must be individually addressed, in patients with nonmetastatic ACC (ENSAT stage I-III) surgery is the treatment of choice. Margin-free (R0) resection provides the best chance to obtain long-term local control [9,10,17] and is independ- ently associated with improved survival [26]. This implies the need for en-bloc multiorgan (i.e., liver, kidney, pancreas, spleen, stomach and colon) and/or vascular (i.e., inferior vena cava) resection in patients with invasion of surrounding structures [27]. Controversial is the need for extended resec- tion in patients with more limited disease (stage II and stage III with T3 tumors) [6,7,28,29]. For the proponents, en-bloc nephrectomy could theoreti- cally allow a more radical operation because of the complete removal of the lymph node of the renal hilum and the treatment of microscopic unsus- pected invasion of the periadrenal fat [6,7,29,30].
It has been recently reported that pre or intra- operative evaluation is insensitive for detection of many stage III ACC because of microscopic invasion [31”]. Indeed, Miller et al. [31""] found that about one third (35/113 - 31%) of their patients presumed to be stage II were upstaged to stage III after patho- logic examination. It should be underlined that in their series one third (17/51 - 33%) of the patients who underwent adjacent organs or vessels resection were pathologic stage II tumors that had no extra- adrenal extension. In addition, only two thirds (34/55 - 61%) of stage III patients underwent extended resection.
Direct invasion of the kidney is rare [29,30], and there is no evidence that nephrectomy may posi- tively influence the oncologic outcome [7].
The role of lymph node dissection in ACC patients without proven or suspected invasion is still unclear [10]. Despite recent reports indicating that loco-regional lymph node dissection may improve tumor staging and lead to a favorable
oncologic outcome [32], there is no precise defi- nition of loco-regional lymph node dissection and no consensus about its role [5,8-11].
As a consequence, in the absence of clear-cut evidence of any benefits in terms of oncologic out- come, extended resection should be performed only when adjacent structures appear pre or intraopera- tively involved [29,30]. For patients with apparently localized disease the adrenal gland should be removed en bloc with the entire retroperitoneal fat pad, which also includes some periadrenal lymph nodes [10,29], in order to obtain microscopically negative margins, even in patients with microscopic extraadrenal invasion. Dissection should respect the rules of oncologic surgery, avoiding direct tumor grasping or fragmentation and tumor capsule effrac- tion [4,5,8,10].
Is the oncologic outcome different between patients with ACC treated by endoscopic adrenalectomy vs. open adrenalectomy?
The only way to definitively answer this question would be a large prospective randomized trial. How- ever, it is not likely to be performed because the disease is rare and most of the diagnosis in localized tumors is pathological. As a consequence, the dis- cussion on this topic should be on the basis of the restrospective analysis of single institution series and multiinstitution surveys.
During the last 2 years, several manuscripts contributed to the debate. Reports from the USA continued to discourage endoscopic adrenalectomy in patients with known or suspected ACC [31”,33”,34"",35”], although in some series from Europe, endoscopic adrenalectomy appeared to be not inferior to open adrenalectomy in terms of oncologic outcome [36”,37”,38”].
In the study of Miller et al. [31""], 156 patients with stage I-III ACC were included: 46 underwent endoscopic adrenalectomy and 110 open adrenalec- tomy. No significant difference was found in terms of overall recurrence rate between endoscopic adrenalectomy and open adrenalectomy after R0 resection (69 vs. 62.5%). Positive margins or intra- operative tumor spill was observed in 30% of endo- scopic adrenalectomy compared with 16% of open adrenalectomy patients, despite larger tumors and more advanced stage tumors in the open adrenalec- tomy group. Time to local recurrence in patients with stage II ACC was shorter after endoscopic adre- nalectomy. Overall survival (OS) for patients with stage II ACC was longer in open adrenalectomy, even in patients with R0 resections. Noteworthy, only a minority of the patients (15.4%) underwent primary resection at the authors’ institution (none
of them endoscopic adrenalectomy). This implies that the great majority of the patients were referred after being operated at nonreferral centers. More- over, in patients with tumors smaller than 10 cm, despite time to initial recurrence being shorter for endoscopic adrenalectomy, no significant differ- ence was found for time to distant recurrence and survival [31""]. Similar results of the same group were reported in another study including 391 patients: open adrenalectomy was associated with improved OS, but disease-free survival (DFS) was similar for both groups [33”]. Of note, the surgical approach was documented only in two thirds of the included patients (241/391) [33”].
Similar findings were observed by Cooper et al. [34”] in their retrospective analysis of 302 patients. All the patients underwent primary surgery with curative intent: 46 endoscopic adrenalectomy and 210 open adrenalectomy at an outside hospital and 46 open adrenalectomy at the authors’ institution. The rate of positive margin was significantly higher and the peritoneal recurrence-free survival shorter in the endoscopic adrenalectomy group. Notewor- thy, median OS was not significantly different between the open adrenalectomy and the endo- scopic adrenalectomy groups, and it has a tendency to be longer in the endoscopic adrenalectomy when compared with open adrenalectomy performed at outside hospital (53.5 vs. 46.0 months), similarly to the overall recurrence rate (76.1 vs. 87.3%) [34""].
In a smaller study including 44 ACC patients (18 endoscopic adrenalectomy and 26 open adrena- lectomy) operated at a single high-volume center, Mir et al. [35”] failed to demonstrate any significant difference in terms of positive margin and recur- rence rate between endoscopic adrenalectomy and open adrenalectomy groups, even if they stated that open adrenalectomy patients had a nonsignificant lower risk of recurrence and improved survival. However, in the interpretation of their results it should be taken into account that endoscopic adre- nalectomy patients were more frequently stage I and II and had a significantly shorter follow-up [35”].
Describing the personal series of nine patients who underwent adrenalectomy for ACC during a 20-years period, Toniato [39] found that most of the patients approached laparoscopically (5/6 - 83.4%) had to be converted to open adrenalectomy and concluded that endoscopic adrenalectomy is inappropriate for patients with suspected or known ACC [39].
Conversely, in a report of a multiinstitutional Italian survey, including 156 patients who under- went R0 resection for stage I and stage II tumors (126 open adrenalectomy and 30 endoscopic adrenalec- tomy), we found no significant difference between
the endoscopic adrenalectomy and open adrenalec- tomy groups in terms of 5-year OS and DFS and in terms of mean time to recurrence and of type of recurrence (local vs. distant) [36”]. Of note, despite this study being multiinstitutional, most of the patients were treated at high-volume centers [40]. In addition, endoscopic adrenalectomy was associ- ated with a better postoperative outcome, as under- lined by the shorter postoperative stay [36”].
Relatively large single institution studies, coming from European countries referral centers obtained similar results.
In their retrospective analysis of a single referral center series of 34 patients with stage I and II ACC smaller than 10 cm (13 endoscopic adrenalectomy and 21 open adrenalectomy), Donatini et al. [37”] demonstrated that endoscopic adrenalectomy is associated with a more favorable early surgical out- come (shorter postoperative stay) than open adre- nalectomy and comparable long-term OS and DFS.
In addition, in their single center study includ- ing 32 patients with stage I-III ACC operated between 1998 and 2011 (17 endoscopic adrenalec- tomy and 15 open adrenalectomy), Fossa et al. [38""] demonstrated that endoscopic adrenalectomy has a more favorable postoperative outcome (shorter operative time and hospital stay; lower transfusion and complication rates) and similar oncologic out- come (including rate of R0 resection, pattern of recurrence, DFS and OS). Noteworthy, in the endoscopic adrenalectomy group, three patients underwent extended resection, confirming previous report that multiorgan resection is feasible by laparoscopy in experienced hands [41].
In summary, the existing literature is inconclu- sive regarding the oncologic outcome of endoscopic adrenalectomy vs. open adrenalectomy in patients with ACC, From the amount of available data, on the one hand it could be extrapolated that in experi- enced centers, oncologic outcome for endoscopic adrenalectomy is not inferior to open adrenalec- tomy, when strict selection criteria and the prin- ciples of oncologic surgery are respected. On the other hand, when performed by nonexperienced surgeons, endoscopic adrenalectomy may be associ- ated with a higher rate of positive margin and tumor bed and/or intraperitoneal recurrence, especially if strict selection criteria and a policy of immediate conversion to open adrenalectomy in case of diffi- cult dissection are not respected.
Where should patients be referred for adrenalectomy for suspected ACC?
Because of the rarity of the disease, ACC patients often encounter physicians who are not familiar
with optimal treatment strategies. Improved sur- vival rate was reported for patients with localized ACC who were followed up prospectively in special- ized centers [42]. Improved survival rate was also reported for a large series of ACC patients treated at a referral center in which patients underwent extended surgeries [17]. Additional studies have also clearly demonstrated that increased surgeon and hospital volume are positively associated with improved patient outcomes following adrenalec- tomy [43,44]. As a consequence, it could be possible to argue an advantage in terms of oncologic out- come for ACC patients who receive early specialized care at high-volume centers. We have evaluated this hypothesis in a study based on a multiinstitutional Italian survey. We observed that patients who underwent surgery at high-volume centers experi- enced a better oncologic outcome, with a signifi- cantly longer time to recurrence and a lower rate of local recurrence [40].
Similar results were observed by Kerkhofs et al. [45”] in patients with stage I-III ACC followed in the National Cancer Registry in the Netherlands. Five-year OS was significantly longer for patients undergoing surgery in a Dutch Adrenal Network hospital than for those having surgery in a non- Dutch Adrenal Network hospital (63 vs. 42%).
These results were probably because of the more comprehensive and multidisciplinary approach at specialized centers, which implies more accurate preoperative evaluation, more aggressive surgical approaches and postsurgical adjuvant treatment strategies [40,45""].
Of note, in the Italian survey, significantly more patients underwent endoscopic adrenalectomy at low-volume centers. On the basis of this obser- vation, it would appear that in nonspecialized centers, a diagnosis of ACC is frequently based on histology following an operation for adrenal inci- dentaloma [40]. Similar findings were observed in a recently published study, based on the data of the USA National Cancer Data Base, in which evaluating a cohort of 2765 ACC patients, Gratian et al. [46”] found that patients treated at high-volume centers less frequently underwent endoscopic adrenalec- tomy, received more aggressive surgical resection and more frequently underwent adjuvant treat- ments. Noteworthy, this more aggressive approach did not translate into better OS.
In summary, on the basis also of the most recent literature, we can speculate that patients observed at specialized referral centers receive a more accurate preoperative workup that allows a better preopera- tive planning which includes the appropriate choice between endoscopic adrenalectomy and open adre- nalectomy, the need for associated en-bloc resection
and lymph node dissection, and a more compre- hensive postoperative treatment. As a consequence, we agree that surgery for suspected ACC should be limited to specialized centers that perform more than 20 adrenalectomies per year and have multi- disciplinary team and facilities [9,11].
CONCLUSION
Because the completeness of the primary surgery is of utmost importance to assure optimal outcome of ACC patients, operation should be accurately planned through a comprehensive preoperative workup. Surgeon experience plays a crucial role and patients with suspected or proven ACC should be referred to surgeons with adequate experience in adrenal surgery [9,11].
In the current literature, there are not conclusive data that allow to definitively specify what is the appropriate role of endoscopic adrenalectomy for ACC. When waiting for further more exhaustive studies, we think that for suspected ACC, smaller than 8-10 cm [8,9,11,24,25,37”] and without pre or intraoperative evidence of local invasion, endo- scopic adrenalectomy (including en-bloc removal of the periadrenal fat pad, eventually associated with loco-regional lymph node dissection) in a refer- ral center seems to be acceptable and may even be preferable in selected cases because of better post- operative outcome [11]. However, before surgery, patients should be accurately informed that endo- scopic adrenalectomy for ACC is still not standard of care. In all other patients with localized ACCs, open surgery, which allows for extended resection, including en-bloc resection of adjacent structures and extensive lymph node dissection, when necess- ary, is the treatment of choice.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.
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