Introduction

Adrenal lesions represent a spectrum of various pathologies, ranging from benign diseases to adrenocortical carcinoma or metastasis. They are frequently incidentally diagnosed and surgery is indicated in case of hormone secretion, risk of malignancy or diagnostic doubt. Regardless of the pathology, adrenal lesions always need a multidisciplinary approach, for their endocrine implications as well as the difficult differential diagnosis and the choice between open and a mini-invasive surgical approach.

Since the first description of Gagner et al. [1] in 1991, the mini-invasive approach to a wide range of adrenal lesions has become more and more frequent. When comparing with the open technique, laparoscopic adrenalectomy seems to offer lower perioperative morbidity and mortality, shorter hospitalization and better cosmetic results. Although now largely established as the gold standard for small and benign adrenal lesions, the laparoscopic approach remains controversial when other adrenal pathologies occur. Open adrenalectomy is still indicated in some cases, because of the possibility of an uncomplete curative resection with the laparoscopic approach. The aim of this review is to emphasize the indications to open adrenalectomy, with particular attention to adrenocortical carcinoma (ACC) and other adrenal pathologies.

Indications

Open adrenalectomy is still performed for many adrenal lesions. Lee et al. [2] considered 669 patients operated in 123 American centers between 2001 and 2004: the overall prevalence of open adrenalectomy was about 46%. A recent survey from Elfenbein et al. [3], based on the American College of Surgeon-National Surgery Quality Improvement Project, stated that among 3.100 adrenalectomies performed by American centers between 2005 and 2010, almost 21% were carried out by a laparotomic approach. These data confirm the increase of the laparoscopic approach, but also emphasize the role of open surgery.

The main indications to open adrenalectomy are (1) general contraindications to laparoscopy; (2) contraindications related to the specific adrenal disease.

General contraindications to laparoscopy

Severe coagulopathies, severe cardiac disease or intracranial hypertension represents nowadays an absolute contraindication to laparoscopic adrenalectomy, except for selected cases. ASA score >3 (p < 0.001) and any bleeding disorder (p = 0.006) are the main patients-related factors influencing the open adrenalectomy in the Elfenbein survey [3]. Other contraindications were a severe heart insufficiency (NYHA class III or IV), a severe respiratory insufficiency or a previous upper abdominal surgery. In particular the patients with severe respiratory failure, once considered an absolute contraindication to laparoscopy, can be sometimes treated through a mini-invasive approach, thanks to the improvement of the surgical and anaesthetic skills. It is well known that laparoscopy brings a lesser abdominal trauma, related to an enhanced postoperative respiratory recovery and a faster mobilization of the patient that results in a smaller incidence of postoperative respiratory complications, especially in the older patients. Some recent cases of personal adrenalectomies, treated with a <7 mm Hg pneumoperitoneum, confirm that respiratory disease could be considered a relative contraindication to laparoscopy, when either the surgical experience (low-pressure pneumoperitoneum, short operative time, possible extraperitoneal approach) or an adequate intraoperative respiratory management are present. A low-pressure pneumoperitoneum adrenalectomy could also be an interesting solution for strongly secreting pheochromocytoma cases, since some authors [4] have demonstrated a less catecholamine release and fewer hemodynamic fluctuations. Other relative contraindications to a mini-invasive approach are the glaucoma, the pregnancy and the presence of a voluminous diaphragmatic hernia.

Disease-related contraindications

Many studies have underlined limits and contraindications to mini-invasive adrenalectomy related to a specific adrenal disease. In the Elfenbein survey [3], the main disease-related factors were a suspected or proven malignancy (p < 0.001), a locally advanced cancer (p < 0.001), adrenal metastases or a very large tumour size. As regards to tumour size, many surgeons have expanded their indications to laparoscopic adrenalectomy; consequently this approach is now used for large adrenal lesions too, especially thanks to new dissection and coagulation devices [5]. Moreover, a clear definition of large adrenal tumour is matter of debate and no exact dimensional cut-off is determined for laparoscopic adrenalectomy. Some authors suggest a 6 or 8 cm threshold, but most authors define as large those adrenal lesions bigger than 5 cm in size [6]. In the literature, few laparoscopic adrenalectomies also for 15-cm lesions are described [7], necessitating longer operative times and higher risks of conversion. Tumour size may increase operative time [8], first for the subverted anatomy, second for the increased surface of dissection. Conversion rates in >5 cm adrenal lesions range from 4 to 16% in different studies [9]. A retrospective study [10] of about 456 laparoscopic adrenalectomies, found that predictive factors for conversion are pheochromocytomas, high body mass index and tumour size >5 cm. Statistical data from Tiberio et al. [11] demonstrated that a tumour size >5.5 cm was an independent factor influencing conversion to open surgery in a laparoscopic cohort of patients.

In our 197 laparoscopic adrenalectomies, 18 were >6 cm in size: we have had an overall conversion rate of 4.1%, no postoperative mortality and an overall major morbidity rate of 5.1%, mainly related to respiratory complications. The higher conversion rate occurred at the beginning of our laparoscopic experience, mainly influenced by the size of the adrenal lesions. Therefore, a certain risk of malignancy must be considered in all >6 cm adrenal lesions. Then, in these cases, the choice of surgical approach should always be preoperatively shared together with a dedicated team: in particular a dedicated radiologist is very important to offer reliable indications about the nature of the adrenal disease. The importance of a multidisciplinary approach finds confirmation in this very large adrenal tumour (Fig. 1), laparoscopically treated only thanks to an accurate preoperative imaging study, suggestive for an hemangioma, instead of an ACC.

Fig. 1
figure 1

Large haemangioma of the left adrenal gland, in which a reliable preoperative diagnosis permitted a laparoscopic approach

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Which kind of lesions?

The main indication to open adrenalectomy is represented by ACC; however, other pathologies can sometimes require a laparotomic approach.

Benign cystic adrenal lesions

Cystic adrenal lesions represent a rare entity, with a reported incidence at autopsy of 0.064 to 0.18%. Incidence of adrenal cysts in adrenal disease is 5.4%, according to various clinical series [12]. Abdominal pain, gastrointestinal symptoms and a palpable mass are the main clinical manifestations, but more than 55% of the cases are asymptomatic. Large cysts have a tendency to develop complications, such as intracystic haemorrhage and rupture, causing a surgical emergency [13]. Computed tomography (CT) may suggest malignancy through calcification, thickness and enhancement of the vesicle wall [14].

Surgical resection of an adrenal cyst has been proposed in case of hormone secretion, size increasing of more than at least 1 cm/year, changes in imaging (haemorrhage and calcification) [14]. Some authors choose laparoscopic adrenalectomy in all patients with adrenal cysts, others prefer adrenal-sparing resections, even for functional cysts [15], suggesting that the preservation of the gland is safe. Open adrenalectomy is mandatory in case of diagnostic doubt, in case of giant cyst interesting surrounding organs or in case of intracystic haemorrhage or rupture, representing a surgical emergency: in this 37-year-old pregnant woman, admitted to our emergency department with haemoglobin levels below 6 g/dl due to a massive intralesional haemorrhage, an open adrenalectomy was necessary, since a rapid laparoscopic control of the bleeding was impossible (Fig. 2).

Fig. 2
figure 2

Massive intralesional haemorrhage of a right adrenal cyst, requiring an emergency open surgery

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Myelolipoma and ganglioneuroma

Adrenal myelolipoma (AM) is a benign lesion representing 4% of all the performed adrenalectomies [16]. The majority of AM are incidentally diagnosed by imaging that shows their typical features (fat within a heterogeneous density showing varying degrees of lipomatous as well as myeloid tissue) [16]. Typically, AMs are unilateral, but bilateral cases occasionally occur [17].

American Association of Endocrine Surgeons guidelines in 2009 recommended adrenalectomy for AM larger than 4 cm [18], while other authors [19] indicated surgery for symptomatic or sizeable (>7 cm) lesions, because of the risk of rupture, abdominal pain and atypical radiological appearance.

Usually large AMs do not represent a contraindication to the mini-invasive surgical approach; in fact they consist of macroscopic well encapsulated fat with a tender texture, enabling an easy laparoscopic mobilization of the mass from adjacent structures. Finally, they have virtually no risk of recurrence.

Shen et al. [20] reported eight patients with AM treated by retroperitoneal laparoscopic liposuction. Mean tumour size was 10.5 cm, ranging from 8 to 14 cm; no recurrence was observed during follow-up. Main indications to laparotomic approach in AM are relative to very giant lesions, in which the size of tumour can interfere with the laparoscopic movements; other indications to open surgery are a retroperitoneal uncontrollable haemorrhage or the tumour rupture in an emergency setting.

Ganglioneuroma (GN) is a rare, differentiated, frequently benign, slow-growing tumour that commonly arises from sympathetic ganglion cells. An open approach is reported in patients with an extensive disease, like the reported case of Vasiliadis et al. [21], concerning an extra-adrenal GN involving the infrahepatic inferior vena cava, superior mesenteric artery and celiac axis. Other authors reported excision of large retroperitoneal GNs extending from the right renal vein to the diaphragmatic hiatus, thus resected with an open approach needing the mobilization of pancreas and liver [22]. Some authors have also described a fractionated resection: the tumour was divided into upper and lower fractions and then incised along the course of the surrounding vessels. The tumour fractions were then resected separately [23]. For this latter technique, the exclusion of malignancy is at least recommended for the high risk of peritoneal seeding while dividing the tumour. It appears to be clear that the open indications to adrenalectomy for GNs are mainly relative to the tumour size and to the surrounding organs implication.

Pheochromocytoma and paraganglioma

Surgical resection is the mainstay of treatment for both benign and malignant pheochromocytoma.

Some papers investigated haemodynamic fluctuations and catecholamine levels during surgery for pheochromocytoma, both in laparoscopic and in open techniques, detecting no differences related to the approach [24, 25]. However, Assalia and Gagner [26] systematic review showed that laparoscopic adrenalectomy for pheochromocytoma was related to a high postoperative complication rate, up to 37% in some series. Moreover, Kalady et al. [27] found out that intraoperative blood loss during the laparoscopic adrenalectomy for pheochromocytoma was significantly higher than for other diseases. Pheochromocytoma is characterized by intense vascularization, and then if an unavoidable intraoperative hypertensive crisis occur, a bleeding can make difficult the laparoscopic haemostasis. Second, pheochromocytoma tend to be associated to a local desmoplastic reaction, creating strong adhesions or fibrosis with the surrounding tissues. Finally, pheochromocytoma can sometimes grow very posteriorly, contracting proximity with inferior vena cava for a long tract; all these situations can suggest an open primary approach, as well as a laparotomic conversion after a mini-invasive initial attempt (Fig. 3).

Fig. 3
figure 3

A large right pheochromocytoma growing posteriorly to the inferior vena cava that necessitated an open adrenalectomy

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Recently published National Comprehensive Cancer Network (NCCN) guidelines suggest that a laparoscopic approach, when safe and feasible, is the preferred treatment even if they stated that an open exploration is always recommended for tumours that have a high risk of malignancy [28]. Conzo et al. [29] suggested that laparoscopic approach could be safely performed also in lesions >6 cm, even if with a higher conversion rate (8.6%). On the other hand, Endocrine Society 2014 guidelines strongly recommend an open adrenalectomy for large (>6 cm) or invasive pheochromocytomas to ensure a complete tumour resection, to prevent a tumour rupture and to avoid a consequent local recurrence [30]. This recommendation is supported by the lack of prospective randomized studies comparing laparoscopic with open adrenalectomy for pheochromocytomas. While safety and effectiveness of laparoscopy is demonstrated, no data regarding oncological outcomes are available and no difference in recurrence rate after open vs. laparoscopic adrenalectomy has been investigated. Kercher et al. [31] suggests that one of the greatest concerns surrounding laparoscopic adrenalectomy for pheochromocytoma is not whether the procedure should be done, but by whom should it be performed. Then, given the relatively low number of operations performed, the obvious potential for morbidity and the risk of recurrence, laparoscopic adrenalectomy for pheochromocytoma should not be performed in low-volume centres or by surgeons with limited laparoscopic experience.

Paraganglioma is a rare catecholamine-producing tumour, localized in extra-adrenal site, mimicking pheochromocytoma. Abdominal paragangliomas are more likely to be malignant and sometimes occur in areas where a laparoscopic approach can be difficult, necessitating experienced laparoscopic surgeons [28]. Then, an open resection is always mandatory especially when the tumour characteristics suggest a malignant pathology, as well as an extended resection including main vessels is indicated (Fig. 4).

Fig. 4
figure 4

Malignant paraganglioma infiltrating the inferior vena cava that necessitated vascular resection: a CT scan; b operative specimen; c vascular reconstruction using a PTFE graft; d postoperative CT scan

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Metastases

Metastases represent frequent adrenal lesions, mainly from lung cancer, breast cancer, melanoma, colon cancer and renal cell cancer [32]. They can be synchronous or metachronous and should be suspected in any patient with an adrenal mass appeared during oncological follow-up [32]. Some authors [33] advocate the role of laparoscopic surgery also in these situations, suggesting that the type of surgical approach is not significantly related to prognosis. Sarela et al. [34] showed that the only poor prognostic factor in these patients is a short disease-free interval from the final treatment of the primary cancer to the diagnosis of the adrenal metastasis. Proper patient selection is thus crucial. Some signs should be taken into account during preoperative workup: the presence of tumour invasion of adjacent organs, lymphadenopathy, invasion of periadrenal fat, tumour size >10 cm and the presence of a renal vein or inferior vena cava thrombus are all certain indications to an open approach. Gryn et al. [35] reported that when adrenalectomy for metastasis is performed by highly experienced laparoscopic surgeons, postoperative complications and positive surgical margins occur only in tumours >7.5 cm and stated that these patients may benefit from an open surgical approach. Moreover, Assalia and Gagner et al. [26] showed that a laparoscopic approach is not always convenient in this kind of lesions because of an increased risk of conversion reaching 14%, and of postoperative complications reaching 42%. An open adrenalectomy is also indicated in synchronous adrenal metastases (Fig. 5). On this latter topic, Barone et al. clearly stated that an aggressive surgical policy have survival benefits also in non-small cell lung cancer metastases, even if a metachronous disease is associated with a longer overall survival [36].

Fig. 5
figure 5

Synchronous liver resection and right adrenalectomy for HCC adrenal metastasis

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Adrenocortical carcinoma

Adrenocortical carcinoma (ACC) represents a rare tumour, counting for less than 5% of all adrenal incidentalomas [37]. ACC prevalence strictly depends on the size of the tumour [38] accounting for 2% of lesions <4 cm, 6% of lesions between 4 and 6 cm, and 25% of lesions >6 cm ACCs can be asymptomatic or present symptoms due to an hormonal secretion. Around 60% of functional ACC expresses a Cushing’s syndrome [39], between 20 and 30% causes virilisation [40] and 10% causes feminization, representing a poor prognostic factor [41].

Then, a correct imaging evaluation is essential, especially for size and radiological appearance, to differentiate between benign and malignant lesions. CT and magnetic resonance (MRI) are currently the gold standard in the assessment of resectability and relationship to other structures [42, 43]. Probably, MRI is the best method to evaluate the lipid content of the mass and to determine invasion to adjacent organs. CT scan can be associated to 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), even if some authors suggest FDG-PET mistakes in differential diagnosis between benign adenomas and pheochromocytomas [44]. Then a multidisciplinary discussion, particularly with a dedicated radiologist should be advocated when an ACC has been suspected. Nowadays, many surgeons enlarge their indications even in potentially malignant primary adrenal tumours, but a laparoscopic adrenalectomy should be offered in carefully selected cases (such as lesions smaller than 8–10 cm and without pre- or intraoperative evidence of local invasion) and only in referral centres with appropriate expertise, to avoid jeopardizing the oncological outcomes [45]. The role of the open adrenalectomy is always mandatory in advanced stages of ACC (Fig. 6), but in the last few years, many authors have analysed the oncological safety of the laparoscopic approach in earlier cases too. A recent study on the European Network for the Study of Adrenal Tumors staging system (ENSAT) stage I/II ACC [46], seemed to demonstrate equivalence on long-term oncological outcomes between laparoscopic and open surgical approach. This study has several biases, such as the retrospective patients’ collection, the small sample size and a small median size of tumours, around 5 or 6 cm in both arms of treatment. The overall level of evidence in the literature is still poor, but a recent meta-analysis on four studies, considering only ENSAT stage I/II ACCs treated by open or laparoscopic adrenalectomy, has shown the relative safety in short-term outcomes of the laparoscopic technique [47]. In fact, postoperative complications, R0-resections, overall survival and disease-free survival were comparable and independent to the procedure. However, the sub-analysis on the long-term outcomes showed that the 5-year survival was more favourable to the open group. In the laparoscopic group, 67% of patients were dead at 5 years, with respect to 51% of the open group (OR 2.17; CI 95% 1.04–4.50, p = 0.040). The oncological risks of a laparoscopic approach were already stated: Miller et al. [48], in a study of 88 patients affected by ACCs treated with the open or laparoscopic approach independent of the size of the tumour, found out that the percentage of positive margins or intraoperative tumour rupture was significantly higher in the laparoscopic group with respect to the open group (50 versus 18%, p = 0.010), even if bigger lesions (average 12.3 cm) in the open group were included. The laparoscopic approach caused a faster local recurrence, with an average of 9.6 months, while 19.2 months in the open group (p = 0.005). The authors performed a sub-analysis of outcomes depending on tumour size; tumours smaller than 6 cm in size presented a 38% of local or peritoneal recurrence at a median follow-up of 36 months in the laparoscopic group, with respect to 20% in the open group. Moreover, when considering tumours larger than 10 cm, the positive margin or the tumour spill rate was 50% in laparoscopy, while they were 7% in cases resected by an open approach.

Fig. 6
figure 6

Giant ACC (>12 cm) dislocating the right kidney and strictly adherent to the inferior vena cava. An open approach was mandatory to achieve a radical exeresis and to avoid a capsule injury with possible tumour spillage: a preoperative CT scan; b surgical specimen relative; c operative field after surgical exeresis

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Based on these data, the issue of local recurrence has become, in the last few years, the primary debate on the surgical approach concerning ACCs. Miller et al. [49] clearly stated that resection of ACC is less complete: a local recurrence occurs sooner and more often after laparoscopic adrenalectomy, even if no adjacent organ or vessels seemed to be involved during the operation. This data is very significant, since in the group no stage I disease were included. This statement was supported by the evidence that average time to recurrence in the tumour bed or like a peritoneal carcinomatosis was significantly shorter (11.7 months) in laparoscopic adrenalectomy (LA) group, with respect to open adrenalectomy (OA) one (29.5 months), with a p value of 0.002. This difference persisted also when R0 resection were analysed, with a statistical difference between LA and OA (12.3 versus 30.5 months, respectively; p = 0.002). Finally, overall survival, especially in stage II carcinomas, was significantly shorter in LA with respect to OA group, independent from resection margin status (50.9 versus 103.1 months; p = 0.002). The open approach seemed also safer for Cooper et al. [50]: the peritoneal recurrence was 54.3% in the laparoscopic group, with respect to 19.6% in the open cases (p = 0.006), suggesting a significant role of the surgical approach in the subsequent onset of peritoneal recurrence. The same results concern recurrences in any site and median recurrence-free survival, with only 10.9 months disease-free in the laparoscopic group, with respect to 19.6 months in the open group (p = 0.005). Finally, patients treated with an open adrenalectomy had had 109.8 median months of overall survival, almost twice longer than the laparoscopic group (53.5 months), even if not reaching the statistical significance. All these observations have been recently confirmed by an extensive meta-analysis made by Autorino et al. [51] that identified in length of hospital stay, the only advantage of laparoscopic adrenalectomy when compared to the open approach. The laparoscopic procedure had a significant higher risk of recurrence as peritoneal carcinomatosis with a relative risk (RR) of 2.39 (CI 95% 1.41–4.04; p<0.001), while no differences were found regarding time to recurrence and cancer-specific mortality rate. Autorino concluded that open adrenalectomy should be still considered the standard of care for the surgical management of ACCs, as it allows a proper radical treatment of the disease. Finally, the recent 2016 NCCN guidelines [28] pointed out the recommendation of an open approach in any kind of ACC for two reasons: the possible requirement of a removal of adjacent structures for a complete resection and the evidence of an increased risk of local recurrence and peritoneal spread when this pathology is laparoscopically treated.

Recurrent adrenocortical cancer

Recurrence after surgically treated adrenal malignancies can occur at any time, mainly represented by loco-regional or peritoneal carcinomatosis. Local recurrence can also occur in R0 resected patients. In a large series of Dy et al. [52] 93/125 (74.4%) patients R0-resected at the time of primary adrenalectomy recurred after a median follow-up of 15 months. Sixty-seven had been surgically re-resected for recurrence through an open approach, with advantages on overall survival. Also, pain and hormonal symptoms improved in 84% of them. Patients with a disease-free survival interval >6 months from the primary adrenalectomy and with a complete resection of the recurrence were those who benefited more. The authors reported improvements in symptoms control also in patients that only received a surgical debulking, suggesting that the criteria for surgery in recurrent ACC could be extended. A multicenter retrospective study of Simon et al. [53, 54] clearly stated that surgery, when it is performed with an open approach, is the best prognostic factor to improve survival, together with a >12 months disease-free interval between initial resection and recurrence. Age, tumour stage, tumour size and Ki-67 were not associated with better overall survival.

Conclusion

Laparoscopic approach for adrenalectomy is becoming increasingly used worldwide. However, the literature points out some precise indications to the open approach. An open adrenalectomy is to be considered in the majority of ACC, independent of its size, considering the poor oncological safety of the laparoscopic approach. Open adrenalectomy should also be taken into consideration in large adrenal lesions, in complicated cysts requiring emergency surgery or when the risk of malignancy cannot preoperatively be excluded. Moreover, in every case of pheochromocytoma, surgeons must consider the possibility of a laparotomic conversion, because of the higher risk of intraoperative bleeding; conversion must also be suggested when the capsule has been incidentally injured. For all these reasons, apart from the choice of surgical approach, every kind of adrenal lesion should be referred to a multidisciplinary evaluation, to share the indication with expert endocrinologists, radiologists and pathologists, together with dedicated surgeons.