Laparoscopic Versus Open Adrenalectomy for Localized/Locally Advanced Primary Adrenocortical Carcinoma (ENSAT I–III) in Adults: Is Margin-Free Resection the Key Surgical Factor that Dictates Outcome? A Review of the Literature

Abstract

Background:

The aim of this study was to review the current literature on the role of laparoscopic adrenalectomy (LA) in the treatment of primary adrenocortical carcinoma (ACC; European Network for the Study of Adrenal Tumors [ENSAT] I–III) in adults.

Materials and Methods:

Nonrandomized controlled trials published between January 1999 and February 2017 were identified by searching the Pubmed, EMBASE, Cochrane Library, and Google Scholar databases. Primary and secondary endpoints included surgical and pathological parameters (patients age, tumor size, ENSAT stage, type of surgical approach, and period of follow-up), surgical outcomes (operative time, estimated blood loss, length of hospital stay, conversion rate to laparotomy, R0 resection, and surgical margin's status), and oncological outcomes (rate of recurrence, disease-free survival [DFS], and overall survival [OS] rates).

Results:

A total of 13 studies encompassing data on 1171 patients were included in the review. Compared with open approach, LA demonstrated lower tumor size, shorter operative time, lower intraoperative blood loss, shorter postoperative hospital stay, and equivalent local recurrence rates. No significant differences were observed between groups treated with an open or laparoscopic approach for the following criteria: R0 surgical resection status, tumor overall recurrence, and postoperative DFS and OS rates.

Conclusions:

LA appears to be equivalent to open method for localized/locally advanced primary ACC (ENSAT I–III) in terms of R0 resection rate, overall recurrence, DFS, and OS, therefore suggesting that the extent of surgery with adequate tumor resection is the predominant endpoint, rather than the surgical approach itself. Multicenter randomized controlled trials with long follow-up time periods exploring the long-term oncological outcomes are required to determine the benefits of the laparoscopic over the open approach in adrenocortical carcinoma.

Introduction

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy, with an annual incidence of approximately 1–2/1,000,000 people worldwide accounting for 0.05%–0.2% of all malignancies. The age distribution is bimodal with a first peak in childhood and a second higher peak in the fourth and fifth decade of life, with a slight female predominance.^1,2 Although most ACCs are sporadic, numerous hereditary syndromes have been associated with this type of cancer including Beckwith-Wideman syndrome, multiple endocrine neoplasia type 1, Li-Fraumeni, congenital adrenal hyperplasia, familial adenomatous polyposis, and Lynch syndrome.^2–4

In 2004, the World Health Organization (WHO) and Union for International Cancer Control (UICC) introduced the first Tumor, Node, and Metastasis (TNM) staging system for ACC based on the traditional McFarlane classification, modified by Sullivan. This classification system has been recently challenged due to a failure to discriminate between the prognosis of patients classified as Stages II and III. Rather, the newly introduced European Network for the Study of Adrenal Tumors (ENSAT) system has become more widely adopted by the ACC community due to its better stratification of patient outcomes. The ENSAT staging system defines ACC disease into four stages. Stage I (≤5 cm) and stage II (>5 cm) tumors are confined to the adrenal gland. Stage III tumors extend into surrounding tissue (e.g., para-adrenal adipose tissue or adjacent organs) or involve loco-regional lymph nodes. Stage IV is reserved for patients with distant metastasis, as lung (40%–80%), liver (40%–90%), and bone (5%–20%).⁵

Although prognosis is certainly dependent on an accurate diagnosis, survival of patients with ACC is mainly associated with both intraoperative findings, and surgical resection technique leading to an R0 margin being one of the most important prognostic factors.^6–9 When surgical excision is deemed complete, the 5-year survival ranges from 32% to 58%, but when incomplete, the median survival is generally <1 year (range, 2–16 months). Unfortunately, even after an apparent complete resection, local or distant relapse occurs in nearly 80% of patients.

Complete surgical excision with microscopically negative margins is therefore the standard of care for localized/locally advanced disease (ENSAT I–III), leading to palliation of symptoms for patients with functional ACCs, and an increased disease-free and overall survival (OS).^8,10 Routine regional lymphadenectomy should be considered for all patients with ACC. In addition to surgical therapy, adjuvant treatment consisting of chemotherapeutic regimens with cytotoxic agents such as single mitotane or combination therapy with streptozocin, etoposide/doxorubicin/cisplatin with or without radiotherapy for patients with high risk tumors such as an R1–R2 resection, in addition to stage III disease and IV metastatic disease. Even patients without these features should be considered for adjuvant therapy since many patients will suffer from tumor recurrence even after seemingly complete removal of ACC.^11,12

There is a consensus among the scientific community that radical adrenal surgery for localized/locally advanced primary ACC (ENSAT I–III) provides a chance for a long-term cure.⁷ However, throughout the past three decades there is an ongoing debate regarding the best surgical approach in such patients. While evidence for invasive-metastatic disease (ENSAT IV) undoubtedly suggests open adrenalectomy (OA), some surgeons have successfully expanded the indications for laparoscopic adrenalectomy (LA) to large, nonfunctioning tumors with a malignant potential and to metastatic lesions given the constantly improved technological advances in the field and the rising technical experience with benign disease. In contrast, other clinicians argue that this approach is absolutely contraindicated.

The aim of this study was to review the current literature on the role of LA versus open technique in the surgical management of primary ACC (ENSAT I–III) in adults. In addition, we sought to define the impact of R0 Resection on Recurrence Rate (RR), Disease-Free Survival (DFS), and OS and define its role as the appropriate surgical technique for ACC.

Materials and Methods

Search strategy and data sources

A PubMed, Embase, Cochrane Library, and Google Scholar database search was performed on literature published from January 1999 to February 2017. Only articles published in English and studies with comparative analysis between open and laparoscopic approach were included in this study. The following key terms were used to perform the research: “adrenocortical cancer,” “laparoscopy” or laparoscopic,” “open,” “laparoscopic versus open,” “adrenalectomy,” “R0 resection,” “margin status,” and “oncological outcome.” Two independent authors (E.M., D.M.) screened all results retrieved by the aforementioned search strategy. Reference lists of the eligible studies and reviews pertinent to our topic were manually assessed to identify potentially eligible articles.

Inclusion criteria

For inclusion in the review, a study had to fulfil the following criteria: (1) original studies comparing OA with LA for ACC with at least five cases per each surgical approach included, (2) if multiple studies were reported by the same institution with overlapping data, the most recent publication was included in the analysis, (3) all titles were screened for articles written in English language, and (4) the surgical procedures were only performed on adult patients (>16 years).

Exclusion criteria

Articles were excluded if (1) they were abstracts, letters, or expert opinions; (2) they reported on adrenalectomy for benign lesions, metastatic ACC (ENSAT IV), or recurrence; (3) there was overlap between authors or centers in the published literature; and (4) there were case reports or less than five cases per each surgical approach included.

Data extraction and tabulation

The following parameters were extracted from each study: study demographics (first author, year of publication, study design, study period, country, number of patients included), surgical and pathological parameters (patients age, tumor size, ENSAT stage, type of surgical approach, period of follow-up), surgical outcomes (operative time, estimated blood loss [EBL], length of hospital stay, conversion rate to laparotomy, R0 resection, surgical margins status), and oncological outcomes (rate of recurrence, DFS and OS rates).

Definitions and statistical analysis

The surgical approach was based on surgeon preference and expertise, and the referral pattern was the same for patients treated with either methodology. The open procedure was, for most of the cases, conducted via anterior subcostal or midline approach, although in few cases was held via posterior or flank approach. Laparoscopic procedure was conducted either via trans-peritoneal (lateral-anterior) or via retroperitoneal approach (lateral-posterior).

Complete (R0) surgical resection was the primary endpoint of this review, along with its association with the RR, DFS, and OS and was defined as no evidence of macro- or microscopic residual disease on the basis of surgical reports, histopathologic analysis, and pre- and postoperative imaging. Recurrence was defined as (1) local, when involving the operative site or regional lymph nodes; (2) peritoneal, when evidence of abdominal carcinomatosis existed; or (3) distant. Disease recurrence was diagnosed on the basis of clinical, laboratory, and radiologic evidence without necessarily requiring histological confirmation of the recurrence.

DFS was defined as the period from surgery date and first time of recurrence or the date of last follow-up without recurrence. The OS was defined as the period between operation date and the death of the patient or the date of the last follow-up if the patient was still alive. Continuous variables were described using mean (±standard deviation) or median (range).

Results

Selection of studies and study characteristics

The initial search for ACC yielded 3173 records. After initial screening based on title and abstract and removal of duplicates, 149 articles were considered and reviewed focused on surgical approach selected. At the end of the process, 19 studies were reviewed in full text and 13 finally met the predefined eligibility criteria. Among studies in which there was overlapping data, only the study with the most recent information was included in the analysis. An overview of the studies, all published between 2005 and 2016, is provided in Table 1. A total of 1171 patients underwent adrenal surgery with a diagnosis of primary ACC, 910 (77%) underwent OA and 261 (23%) LA. Four of the studies were conducted in the United States, one both in Israel and Canada, three in France, three in Italy, one in Germany, and one in Norway.

Table 1.

Characteristics of the Included Studies

Study (Ref.)	Study design	Country	Year of publication	Study period	No. of patients with ACC	Surgical approach (OA:LA), n (%)
Brix et al.³³	Retrospective case control	Germany	2010	1996–2009	152	117 (77):35 (23)
Cooper et al.³⁰	Retrospective case control	Texas, United States	2013	1993–2012	302	256 (85):46 (15)
Donatini et al.³⁴	Retrospective case control	France	2013	1985–2011	34	21 (61):13 (39)
Fossa et al.²⁰	Retrospective case control	Norway	2013	1998–2011	32	15 (47):17 (53)
Gonzalez et al.⁴⁰	Retrospective case control	Texas, United States	2005	1991–2004	139	133 (95):6 (5)
Kirshtein et al.¹⁴	Retrospective case control	Israel, Canada	2008	1995–2005	12	7 (58):5 (42)
Leboulleux et al.²⁹	Retrospective case control	France	2010	2003–2009	64	58 (90):6 (10)
Lodin et al.¹⁵	Retrospective case control	Italy	2007	1997–2005	12	7 (58):5 (42)
Lombardi et al.³²	Retrospective case control	Italy	2012	2003–2010	156	126 (80):30 (20)
Miller et al.³⁵	Retrospective case control	Michigan, United States	2012	2005–2011	156	110 (70):46 (30)
Mir et al.¹³	Retrospective case control	Cleveland, United States	2012	1993–2011	44	26 (59):18 (41)
Porpiglia et al.³⁸	Retrospective case control	Italy	2010	2002–2008	43	25 (58):18 (42)
Vanbrugghe et al.³⁷	Retrospective case control	France	2016	2002–2013	25	9 (36):16 (64)
Total = 13					1171	910 (77):261 (23)

ACC, adrenocortical carcinoma; LA, laparoscopic adrenalectomy; OA, open adrenalectomy.

Clinicopathological characteristics

The general characteristics of the surgical groups are described in Table 2. The mean age of patients at the time of surgery was 46.9 years for the open approach group and 49.4 years for the laparoscopic group. Tumor stage was classified using the ENSAT (2008) classification system with histological confirmation of surgical specimen in combination with preoperative biochemical work-up and imaging along with patients of all stages (I–IV) included in the various studies. Median tumor size was 10.78 cm for OA group and 6.75 cm for LA group.

Table 2.

Clinicopathological Characteristics of the Included Studies

Study (Ref.)	Mean age (OA:LA), years	Tumor stage (ENSAT)	Tumor size (OA:LA), cm, median	Follow-up (OA:LA), months, median
Brix et al.³³	52.3:50.7	I–III	8:6.2	32:64
Cooper et al.³⁰	46.5:45.8	I–IV	12:8	35.5:29.2
Donatini et al.³⁴	44:46	I–II	6.8:5.5	57:80
Fossa et al.²⁰	52:45	I–III	13:8	60:60
Gonzalez et al.⁴⁰	46	I–IV	13:6	28:21
Kirshtein et al.¹⁴	40:56	I–IV	8:4	NR
Leboulleux et al.²⁹	54	I–IV	14:7.0	35
Lodin et al.¹⁵	47.7:47.4	I–IV	8.7:5.8	NR
Lombardi et al.³²	46.6:52.2	I–II	9.04:7.73	40:50
Miller et al.³⁵	47:50	I–III	12.0:7.4	29.5:19
Mir et al.¹³	48:53	I–IV	13:7	31:18
Porpiglia et al.³⁸	41.3:47	I–II	10.5:9.0	38:30
Vanbrugghe et al.³⁷	44.31:48.9	I–III	11.6:6.2	52.9:36.4

ENSAT, European Network for the Study of Adrenal Tumors; LA, laparoscopic adrenalectomy; NR, not reported; OA, open adrenalectomy.

Operative outcomes

The mean operative time was provided in only five studies (<50%) and ranged from 129 to 272.5 minutes for the open approach and between 133 and 297.5 minutes for the laparoscopic approach. One of the studies reported a longer operative time both in the OA and LA group.¹³ The EBL was reported in only four studies and ranged from 550 to 1700 mL in the OA group versus 200 to 1500 mL in the LA group. The conversion rate was documented in nine studies with a mean conversion rate of 11%. The length of hospital stay was reported in six studies, with mean hospital stay being 8.25 days in OA group and 4.7 days in the LA group (Table 3).

Table 3.

Perioperative Outcomes of the Included Studies

Study (Ref.)	Operative time (OA:LA), minutes	Estimated blood loss (OA:LA), mL	Conversion rate, %	Length of hospital stay (OA:LA), days
Brix et al.³³	NR	NR	34	NR
Cooper et al.³⁰	NR	NR	NR	NR
Donatini et al.³⁴	NR	NR	0	9:7
Fossa et al.²⁰	230:150	1700:400	11	13:6
Gonzalez et al.⁴⁰	NR	NR	16	NR
Kirshtein et al.¹⁴	170:153	550:200	7	7:2
Leboulleux et al.²⁹	NR	NR	NR	NR
Lodin et al.¹⁵	161:133	1500:900	4	5.2:4
Lombardi et al.³²	129:135	NR	0	9.3:5.3
Miller et al.³⁵	NR	NR	NR	NR
Mir et al.¹³	272.5:297.5	1100:1500	27	6:4
Porpiglia et al.³⁸	NR	NR	NR	NR
Vanbrugghe et al.³⁷	NR	NR	0	NR

LA, laparoscopic adrenalectomy; NR, not reported; OA, open adrenalectomy.

Surgical and oncological outcomes

Data related to surgical and oncological outcomes are reported in Table 4. The margin status leading to complete R0 surgical resection or not, was provided in all but 2 of 13 studies.^14,15 Among 910 patients who had an OA for ACC, 896 patients had reported data on resection status and 649 (72%) patients had an (R0). Among the 261 patients who had an LA for ACC, 251 had reported data on resection status and 182 (72%) had a complete (R0) resection. Overall incidence of recurrence was provided in 11 studies and ranged from 24% to 100% for OA group versus 22% to 100% for the LA group. DFS was reported in 11 studies and ranged from 8.1 to 48.5 months in the open group versus 6.1 to 61.17 months in the laparoscopic group. OS was documented in nine studies and ranged from 36.5 to 103.1 months in the open group versus 27.5 to 108 months in the laparoscopic group.

Table 4.

Surgical and Oncological Outcomes of the Included Studies

Study (Ref.)	R0 resection (OA:LA), n (%)	Overall recurrence rate (OA:LA), n (%)	Local recurrence rate (OA:LA), n (%)	Disease-free survival (OA:LA), months, median (%)	Overall survival (OA:LA), months, median (%)
Brix et al.³³	64:24 (55:69)	81:27 (69:77)	(38:50)	21.5–24.2	NR
Cooper et al.³⁰	134:25 (52:71)	87.3:58.7:76.1^a	NR^a	9.5:19.5:10.9^a	46:109.8:53.5^a
Donatini et al.³⁴	21:13 (100:100)	5:4 (24:31)	2:1 (9:7)	47:46	(81:85)
Fossa et al.²⁰	12:12 (80:70)	15:12 (100:70)	1:1 (6:5)	8.1:15.2	36.5:103.6
Gonzalez et al.⁴⁰	133:6 (100:100)	115:6 (86:100)	51:3 (38:50)	13:NR	43:NR
Kirshtein et al.¹⁴	NR	NR	NR	NR	(5)
Leboulleux et al.²⁹	37:5 (63:83)	(27:67)^b	(72:34)	20^b	(38:5)
Lodin et al.¹⁵	NR	NR	NR	Up to 58	NR
Lombardi et al.³²	126:30 (100:100)	48:8 (38:26)	14:4 (11:13)	48:72 (38.3:58.2)	60:108 (48:67)
Miller et al.³⁵	72:26 (65:56)	(40:85.7)	NR	Stage II = 30.5:11.7, Stage III = 13.1:6.1	Stage II = 103.1:50.9, Stage III: 43.7:27.5
Mir et al.¹³	16:11 (61:61)	(27:22)^c	12:10 (46:55)	13.8:9.7 (60:39)	(54:58)^c
Porpiglia et al.³⁸	25:18 (100:100)	16:9 (64:50)	6:6 (24:33)	18:23	NR
Vanbrugghe et al.³⁷	9:12 (100:75)	4:6 (44.4:37.5)	0:2 (0:12.5)	40.45:61.17 (55.6:62.5)	70.1:67.3

Three groups OA index:OA outside:LA.

Peritoneal carcinomatosis.

Adjustment for stage resulted in statistically significant differences.

LA, laparoscopic adrenalectomy; NR, not reported; OA, open adrenalectomy.

Discussion

Adrenal surgery has a long history, with the first adrenalectomy described in 1889 by Thonton.¹ The first successful adrenalectomy was carried out by Mayo and Roux for pheochromocytoma in 1927.² For decades, multiple changes to adrenal surgery were developed eventually leading to the first LA described by Gagner et al. in 1992.¹⁶ The introduction of a minimally invasive approach revolutionized adrenal surgery. Since then, LA has become the gold standard of care for the management of benign adrenal tumors.¹⁷ A number of studies have demonstrated its advantages over laparotomy including reduced blood loss, decreased perioperative complications and postoperative pain, shorter recovery time and hospital stay, improved cosmetic result, and more efficient use of healthcare expenditure.^14,18–20

LA is an established procedure and can be performed using a trans-peritoneal (anterior/lateral) or retroperitoneal (lateral/dorsal) approach.²¹ While each approach has its relative advantages and potential limitations, comparative studies had demonstrated no differences in terms of perioperative outcomes.^22–24 The recent wide adoption of the robotic surgical system, especially among urologists, has found its way into adrenal surgery. In addition, single-port surgery has gained increased adoption as the latest addition to the minimal invasive techniques, as progress is made in skills, instruments, and technology.^25,26

The basic principle of LA is to perform gentle and elegant dissection of the surrounding tissues away from the adrenal mass avoiding tumor rupture or excessive release of catecholamines during aggressive manipulation.²⁷ Another principle is the early control of the main adrenal vein to avoid an intraoperative hypertensive crisis secondary to catecholamine release. A complete laparoscopic resection (R0) and the use of an entrapment sac for specimen extraction, in addition to wound protection have further made the laparoscopic approach a reliable technique for malignant tumors.^28,29 Nevertheless, the laparoscopic approach has been widely embraced from the clinical community for the management of large, nonfunctioning tumors with high potential for malignancy and metastatic lesions.^30,31

Several studies have demonstrated the feasibility, safety, and potential benefits of laparoscopic surgery in the treatment of adrenocortical cancer provided that the surgeon has adequate experience and a low threshold for conversion when the local conditions demand it.^20,32–34 However, some results are conflicting.^29–31,35

Therefore, in this study, we reviewed the current literature with the aim of summarizing the role of laparoscopic radical adrenalectomy in adrenocortical cancer. The median operative time and the EBL were both lower in LA compared with the open method in most comparative studies. The outcome of lower operative time can be probably explained by the shorter incisional surface and the smaller tumor size in the laparoscopic approach. The reasons for the reduced blood loss in the laparoscopic group include less traumatic surface, better visualization and more precise and delicate dissection with the laparoscopic instruments.³⁶ Nevertheless, <50% of the studies provided data with regards to these two variables, thus significant biases may be possible with these observations. Furthermore, the duration of hospital stay as an additional important outcome variable, affecting patient satisfaction and cost analysis, was reported in 50% of the studies and was also shorter with laparoscopic approach compared with the standard open technique.

The primary objective of this study was to define data regarding R0 surgical resection and assess results such as overall the RR, DFS, and OS. Out of 896 patients on undergoing OA for ACC with reported data concerning resection status, a total of 649 were offered a complete (R0) resection (72%). In an amount of 251 patients on undergoing LA for ACC with reported data concerning resection status, a total of 182 were offered a complete (R0) resection (72%). Hence, the present review strongly suggests that there is no significant difference between OA and LA approach concerning the achievement of R0 resection throughout the literature. Furthermore, the overall analysis of the RR, DFS, and OS in the present review displayed no major differences between the OA and LA group, therefore suggesting the safety and efficacy of a laparoscopic versus an open technique.^20,34,37

Analyzing overall recurrence, DFS, and OS, there is an unambiguous effect of the R0 resection and margin status on these variables (Table 4). Series with high grade of achievement of R0 resection are considerably accompanied by lower RR and simultaneously higher DFS and OS rates^32,34,37,38 and vice versa.³³ Studies with similar results regarding R0 resection between the two groups, also demonstrate similar results regarding RR, DFS, and OS.^{13,32,34,37,38} These observations suggest that since R0 resection is achieved, there is no major difference between the OA and LA approach with regards to the outcomes (RR, DFS, and OS) associated with each of the methods.

Some of the studies nevertheless had equivocal results^29,35 with higher RR and lower DFS and OS for the LA group, even though the R0 resection status appeared to be higher or equal with the OA group. This may be related to the low median period of follow-up in these two studies or the inclusion of larger and probably of higher malignant potential of tumors resulting in increased overall morbidity and mortality.

It has been advocated in the literature that the pneumoperitoneum may favor the transit of malignant cells intraperitoneally and free intraabdominal cancer cell implantation at the wound site or in the abdominal cavity. Aerosolization of tumor cells is therefore considered possible but implies previous tumor disruption during the dissection.^29,39 With regards to our observations concerning local/peritoneal recurrence, six out of thirteen studies identified higher rates of recurrence for the laparoscopic group with a decreasing tendency in the more recent studies.^{33,35,37,38,40,41} This possibly implies that the continuously increasing knowledge on this issue plus the progressive improvement of surgical skills and learning curves can confine this phenomenon, even though it does not appear to affect substantially the overall RR, DFS, and OS reported in the literature.

This study has several limitations. All the included trials were observational with a relatively low total number of patients and their results cannot be generalized to that extent of randomized controlled trials. Moreover, there was heterogeneity between the two groups since patients characteristics were not always possible to match. In addition, there were few studies with partially reported data regarding oncological outcomes. Finally, between individual studies, the follow-up time varied significantly.

Conclusions

ACC is a highly malignant tumor of the adrenal cortex necessitating complete surgical excision with microscopically negative margins. LA appears to be equivalent to open method for localized/locally advanced primary ACC (ENSAT I–III) in terms of R0 resection rate, overall recurrence, DFS, and OS, therefore suggesting that the extent of surgery with adequate tumor resection is the predominant endpoint, rather than the surgical approach itself. Multicenter randomized controlled trials with long follow- up time periods exploring the long-term oncological outcomes are required to determine the benefits of the laparoscopic over the open approach in ACC.

Footnotes

Disclosure Statement

No competing financial interests exist.

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