Langenbecks Arch Surg (2012) 397:179–194 DOI 10.1007/s00423-011-0889-1 REVIEW ARTICLE Surgical management of adrenal metastases Juan J. Sancho & Frédéric Triponez & Xavier Montet & Antonio Sitges-Serra Received: 12 July 2011 / Accepted: 30 November 2011 / Published online: 16 December 2011 # Springer-Verlag 2011 Abstract Purpose This paper aims to review controversies in the management of adrenal gland metastasis and to reach an evidence-based consensus. Materials and methods A review of English-language studies addressing the management of adrenal metastasis, including indications for surgery, diagnostic imaging, fineneedle aspiration, surgical approach, and outcome was carried out. Results were discussed at the 2011 Workshop of the European Society of Endocrine Surgeons devoted to adrenal malignancies and a consensus statement agreed. Results Patients should be managed by a multidisciplinary team. Positron emission tomography coupled with computed tomography (PET/CT) scanning is the technique of choice for suspected adrenal metastasis. When PET/CT is This paper was presented at the “Update in Malignant Adrenal Tumours Workshop” organised by the European Society of Endocrine Surgeons (Lyon, France, May 12–14, 20011). not available or results are inconclusive, the CT scan or magnetic resonance imaging can be used. Patients should undergo complete hormonal evaluation. Adrenal biopsy should be reserved for cases in which the results of noninvasive techniques are equivocal. If malignancy has been reliably ruled out, patients with adrenal incidentalomas should be managed like noncancer patients. Conclusions A patient with suspected adrenal metastasis should be considered a candidate for adrenalectomy when: (a) control of extra-adrenal disease can be accomplished, (b) metastasis is isolated to the adrenal gland(s), (c) adrenal imaging is highly suggestive of metastasis or the patient has a biopsy-proven adrenal malignancy, (d) metastasis is confined to the adrenal gland as assessed by a recent imaging study, and (e) the patient’s performance status warrants an aggressive approach. In properly selected patients, laparoscopic (or retroperitoneoscopic) adrenalectomy is a feasible and safe option. J. J. Sancho : A. Sitges-Serra Endocrine Surgery Unit, Department of General Surgery, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain Keywords Adrenal metastases . Incidentaloma . Adrenal biopsy . Adrenal imaging . Adrenal malignancy F. Triponez Department of Endocrine and General Surgery, Hôpitaux Universitaires de Genève, Genève, Switzerland Introduction X. Montet Department of Radiology, Hôpitaux Universitaires de Genève, Genève, Switzerland J. J. Sancho (*) Unidad de Cirugía Endocrina, Servei de Cirurgia General i Digestiva, Hospital del Mar, Passeig Maritim 25-29, 08003 Barcelona, Spain e-mail: jjsancho@gmail.com The adrenal gland is a potential site of metastasis from various malignancies. Metastases to the adrenal gland are the second most common type of adrenal masses after benign adenomas, isolated metastases are rare and most adrenal metastases are seen in patients with disseminated cancer [1]. Patients treated for solid organ malignancies undergo surveillance for local recurrence or metastases for extended periods. Imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scanning are typically 180 used and therefore the prevalence of incidentally discovered tumours is increasing [2].The adrenal gland is unusual in that it is not only a common site for metastases but frequently harbours incidental benign tumours. These masses are a diagnostic challenge for the physician and a source of anxiety for the patient [2] The decreasing mortality rates in cancer patients leads to a situation where metastases in general and metastases to the adrenal gland in particular, are becoming more frequent. On the other hand, metastases are likely to be detected earlier because of protocolized follow-up approaches with highly sensitive and reliable methods. However, there is a need for better understanding of the issues associated with the management of these patients especially the choice of biochemical tests, imaging techniques, and appropriate treatment options. Usually, the primary cancer tumour has already been recognised when a potential adrenal metastasis is discovered [3, 4] and it often indicates widespread disease. However, isolated adrenal metastases can occur and can provide an opportunity to improve the prognosis for selected patients [5, 6]. There are numerous reports of patients who remain cancer-free for many years after resection of isolated adrenal metastasis. It has been argued that this longer-term survival is the result of selecting patients with less aggressive tumours who would have survived just as long without resection [7]. The counter argument is that long-term disease-free survival achieved after resection of metastasis to other organs equally applies to resection of isolated metastasis to the adrenal gland. Because of the low occurrence of isolated adrenal metastasis, the feasibility of a randomised trial to assess the long-term outcome of surgical resection versus observation seems unlikely. For this reason, current knowledge is based on the retrospective series of patients who underwent resection of isolated metastasis to the adrenal glands. Differentiation of a metastatic tumour from a primary adrenal mass can be challenging and requires the selective use of radiologic imaging studies, serologic testing and, in selected cases, adrenal biopsy. The use of more sensitive imaging techniques, including PET, magnetic resonance imaging (MRI), and spiral or thin-cut CT has been associated with the detection of small adrenal metastatic lesions, probably undiagnosed before the introduction of these techniques. Furthermore, radio-imaging data can exclude patients with multiple metastatic lesions who are likely to develop recurrences and identify small lesions that are candidates for resection. Patients with adrenal metastases require multidisciplinary evaluation to determine the appropriateness of surgical intervention. Patients with metastases in multiple sites or extensive tumour burden should be treated with systemic chemotherapy or palliative supportive care [1]. Langenbecks Arch Surg (2012) 397:179–194 Prevalence Metastases to the adrenal gland are the second most common type of adrenal masses after adenomas [1]. In the large classical autopsy-based reviews of patients with malignancy, metastases to the adrenal glands were found in 10–27% of patients [8, 9]. The rich sinusoidal blood flow and the multiple pathways of arterial blood supply may explain this high incidence. When dealing with potential adrenal metastasis, three different scenarios may be encountered. 1. The oncological patient has an adrenal mass usually discovered during follow-up. The main question in this scenario is whether this nodule is an adrenal metastasis or not as the generally accepted probability is about 50% [10, 11]. However, in one study where the probability of adrenal metastasis was 52%, only patients referred for surgical resection were considered and patients whose adrenal nodule was evaluated as benign were not taken into account [12]. Moreover, this study was carried out over a long period (1971–2000) during which there were remarkable improvements in the accuracy of imaging studies that allowed more adrenal nodules to be identified. Therefore today, the a priori risk of metastasis in a patient with an adrenal nodule and a history of cancer is probably lower than 50%, except for patients with lung cancer [13]. 2. The patient has an adrenal metastasis from a known or highly suspected primary origin. The question is whether the adrenal metastasis is solitary as the oncological approach is typically very different if the adrenal metastasis is the only secondary location. In many of these cases, a surgical resection could be proposed first. On the other hand, in most patients with metastases in other organs, the oncologic approach will be primarily nonsurgical. It is therefore of utmost importance to identify other metastatic locations before offering an adequate treatment. 3. The patient has an adrenal incidentaloma that appears suspicious on imaging but no oncologic history. The question is whether it is useful to search for a primary tumour. In the study of Lee et al. [3], only four (0.2%) of 1,715 patients with extra-adrenal cancer had neoplastic spread limited to the adrenal gland at the first evaluation. All four patients had large tumours (>6 cm) and clinical manifestations, so these adrenal metastasis could not be considered as incidentaloma [3]. There is no need to search for a primary tumour in the presence of a true incidentaloma. Origin In the Western hemisphere, patient-based series of tumours that metastasise to the adrenal glands include carcinomas of Langenbecks Arch Surg (2012) 397:179–194 the breast, lung, gastrointestinal tract, skin (melanomas), and kidney. Lung (39%) and breast (35%) cancers account for most adrenal metastases. Also, adrenal metastases are documented in up to 40–to 50% of patients with melanoma, hepatocarcinoma, or renal cancer [14]. Autopsy series revealed adrenal gland metastases in 10–59% of patients with nonsmall cell lung cancer and in 50% of patients with malignant melanoma [5] [6]. When adrenalectomy associated to ovariectomy was performed on breast cancer patients to eliminate all oestrogen sources, it yield a prevalence up to 50% [15]. A review of the clinical studies published shows that the relative prevalence of each primary malignant tumour varies according to the source of data and the geographic origin. For example, an excellent retrospective review of 464 patients with adrenal metastasis from a single centre in Hong Kong reported a high prevalence of liver/biliary tree and gastroesophageal cancers, and a paucity of breast cancer and melanoma [16]. Overall, the relative proportion of each origin seems to mirror the prevalence of each advanced primary tumour for a given time period and location. Metastases to the adrenal glands are frequently bilateral. Kocijancic et al. [17] described a group of 50 patients with nonsmall cell lung cancer in whom adrenal metastases were detected. In 20 patients metastases were ipsilateral, in 15 contralateral, and in 15 bilateral. Although most adrenal metastases are undoubtedly of haematogenous origin, some may develop via lymphatic spread from the lung [18]. Lymphatic drainage between the lung and the retroperitoneum is well described [19]. A large autopsy study found a relationship between ipsilateral adrenal metastases and limited metastatic progression. Widespread metastatic disease was associated with contralateral or bilateral adrenal metastases supporting the case that some ipsilateral adrenal metastases came by a lymphatic pathway [20]. If lymphatic spread to the adrenal glands truly does occur, the metastatic pathophysiology would be more regional than distant in nature [21]. Clinical manifestations and functional diagnosis From a clinical point of view, isolated adrenal metastasis can be synchronous (discovered at the time of the primary cancer or within 6 months after identification of the primary tumour) or metachronous (found after a disease-free interval [DFI] of more than 6 months). Most patients (95%) with adrenal metastases are asymptomatic at the time of diagnosis [16]. In cases of bilateral metastases to the adrenal glands, symptomatic hormonal insufficiency (unexplained and protracted nausea, vomiting and weakness, hyponatremia and normal potassium levels) or a frank Addisonian crisis [22] 181 may develop and should be treated with substitution doses of glucocorticoids before and after adrenalectomy. The relative low incidence (2–6%) of Addison’s disease in adrenal metastases may be attributed to the fact that over 90% of the adrenal parenchyma must be destroyed before there is functional adrenal cortical loss. In addition, signs and symptoms of Addison’s disease may be masked or overlooked in patients with advanced malignancies [16]. Occasionally, symptomatic patients have back pain [14, 23, 24] and/or retroperitoneal haemorrhage [25]. Functional assessment Functional testing is paramount to rule out adrenal dysfunction, as up to 48% of adrenal masses in patients with a known malignancy may be true incidentalomas [12]. Assessment of plasma-free levels of metanephrines and normetanephrines together with confirmatory urinary catecholamines and metanephrines levels is mandatory to rule out pheochromocytoma [26]. Complete endocrine assessment should also include measurements of urinary free cortisol levels and the overnight 1 mg dexamethasone suppression test. If the patient is hypertensive, measurement of serum electrolytes, determination of plasma renin activity, and aldosterone concentration are required [27]. All patients with suspected bilateral adrenal involvement should undergo evaluation for adrenal insufficiency [10, 16]. Imaging techniques In the evaluation of potential adrenal metastasis, three imaging studies are particularly useful: CT, MRI, and PET. The most frequent benign adrenal nodule is a cortical adenoma and, in this case, imaging studies are needed to differentiate between adrenal cortical adenoma and adrenal metastasis. Morphologic features can sometimes be helpful. However, given that most metastatic nodules exhibit smooth contours without spread to the adjacent organs, imaging studies will provide information about different aspects, including morphologic features, intracellular lipid content, contrast washout behaviour, and metabolic activity [28]. Morphologic features Firstly, before ordering new (and sometimes expensive) radioimaging studies, it is important to assess data provided by previous examinations. Most of the time, even regular thorax CTs will include the upper abdomen and the adrenal glands. An adrenal nodule that increases in size over 6 months is highly suspicious except in the “obvious” cases of adrenal haemorrhage. On the other hand, an adrenal 182 Langenbecks Arch Surg (2012) 397:179–194 nodule that was present at the time of diagnosis of the primary tumour and that has remained stable for years is very unlikely to be malignant, and probably further evaluation is not necessary. Lesions of >4 cm and particularly those >6 cm have a very high risk of malignancy [11]. Locoregional invasion, grossly irregular shape and/or the presence of large necrotic areas in the mass are highly suggestive of malignancy [29]. However, most metastases have smooth borders and do not invade neighbouring organs. Moreover, most adrenal metastases are homogeneous at an early stage. Adrenal shape, borders, and volume can be accurately assessed with multiplanar reformation and volume rendering tools, using currently standard multidetector CT images [28]. Intracellular lipid content About 70% of adrenal cortical adenomas are lipid-rich adenomas in contrast to malignant lesions, which are lipid poor [30–32]. CT and MRI can use these characteristics to differentiate between benign and malignant lesions. The high lipid content reduces the unenhanced CT density [33]. In 1998, Boland et al. [34] performed a metaanalysis and showed that using a threshold of 10 HU, the sensitivity was 71% and the specificity 98%. This threshold of 10 HU is the standard currently used by radiologists to differentiate lipid-rich adenomas from other adrenal lesions on unenhanced CT studies [29]. Some authors have described a more complex analysis of adrenal fat using a CT characterisation with histogram analysis method, reporting an increased sensitivity while the high specificity was maintained [35]. However, other authors could not confirm these results and this technique are not used in routine clinical practice [36] (Fig 1). Dual-energy CT can be used to detect fat in adrenal lesions. This technique uses the principle that the differences in X-ray attenuation decrease with an increase in the energy of X-ray used (see the study of Coursey el al. [37] for technical details). It can be applied to quantify fat in tissues by measuring the difference in CT attenuation on images acquired at 140 and 80 kg voltage peaks. A difference of attenuation greater than 6 HU indicates that a high amount of fat is present in the lesion [28]. These principles have been known for a long time but it is only very recently that they could be used reliably for adrenal imaging thanks to new technology that allows simultaneous (or near simultaneous) image acquisition with two different energies [37]. There is only one published study of 31 adrenal nodules, which showed an increase in attenuation in all metastatic lesions and a decrease in attenuation 100% specific for the identification of benign lesions [38]. Chemical-shift MRI also uses intracellular fat to characterise adenoma by exploiting different resonant frequencies Fig. 1 A 71-year-old patient with a right nonsmall cell lung cancer and a synchronous right adrenal metastasis. a Fused PET-CT image of the lung showing a 5.2-cm mass in the right lower lobe of the right lung. The maximal SUV of this mass was 35. b Unenhanced CT image of the upper abdomen showing a 2.2-cm right adrenal nodule. This nodule has a regular shape and is homogenous however its attenuation value was 36 HU. c Fused PET-CT image of the upper abdomen showing that the nodule was highly FDG-avid, with a SUV max of 32 Langenbecks Arch Surg (2012) 397:179–194 183 of fat and water protons in a given voxel [29, 39]. Fat and water signals cancel each other during out-of-phase MRI images. The signal loss can be measured quantitatively but most radiologists evaluate the change visually using muscle or spleen as the internal reference organ [28] and this has been demonstrated to be an effective method [40]. The sensitivity and specificity of chemical-shift MRI are similar to those of unenhanced CT for lipid-rich adenomas, although it may be superior for lipid-poor adenomas [41]. Contrast washout behaviour Malignant lesions have abnormal vasculature with a high microvascular density leading to a slow blood flow and a high endothelial permeability that result in accumulation of contrast material in the lesion [28]. Adrenal adenomas enhance rapidly and also show a rapid loss of contrast medium, while malignant lesions also enhance rapidly but show a slower contrast washout [29]. The ratio of attenuation between washout-delayed scans and initial contrastenhanced images can help differentiate benign from malignant lesions [30, 39, 42]. These washout properties can also be used in MRI studies, but the diagnostic accuracy is lower [43]. If no unenhanced CT images are available, the relative percentage of enhancement washout is used. Delayed images taken at 10, 15, or even 60 min can be used. The most common criterion is a >40% of enhancement washout on 15-min delayed images (96% sensitivity and 100% specificity) [30]. The main advantage of this technique is that it can also accurately predict the benign nature of approximately 30% lipid-poor adenomas [29]. Therefore, a combination of unenhanced CT images and washout characteristics can correctly discriminate nearly all adrenal adenomas from malignant lesions (Fig. 2). Metabolic activity Most adrenal cortical adenomas have a very low metabolic activity, whereas the majority of malignant lesions have a high metabolic activity. However, a small size or large areas of necrosis and haemorrhage, as well as metastases from primary cancers that are not PET-avid (carcinoid tumours, bronchioloalveolar type of nonsmall cell lung cancer, renal cell cancer) can give false-negative results [44–46]. In addition, inflammatory processes (tuberculosis, sarcoidosis) Fig. 2 A 64-year-old patient with a right metachronous adrenal b metastasis, 2 years after right upper lobectomy for a nonsmall cell lung cancer pT1N0. a Enhanced CT image showing a 8.5 cm irregular and heterogenous right adrenal mass. b Delayed (15 min) enhanced CT and peri-adrenal abnormalities can give false-positive image showing the same mass. The relative washout was 26% c Fused results on PET scans [29]. Besides these exceptions, many PET-CT image of the same mass. Note the non-avid centre of the mass (necrosis). The SUV max was 8.2 studies have shown that PET, and particularly PET/CT, can 184 reliably differentiate benign from malignant lesions with sensitivity between 80% and 93% and specificity close to 100% [28, 29, 45, 47–51]. The use of PET/CT seems to offer clear advantages over PET alone as it delineates the anatomic location of hypermetabolic spots identified on PET. Furthermore, all aforementioned criteria for CT (unenhanced attenuation values, washout percentage, etc.) can be assessed at the same time [50] avoiding some of the caveats of PET. A standardised uptake value (SUV) adrenal/liver ratio >1.0 is the criterion used in most studies to differentiate benign from malignant lesions [29, 52], although other criteria, such as the maximum SUV value [50] or SUVadrenal/liver ratio up to 1.8 [53] have been proposed. The greatest advantage that PET has over unenhanced CT is that a lipid-poor adenoma behaves in the same way as a lipid-rich adenoma [50]. PET/CT is the technique of choice because it not only allows characterization of an adrenal nodule but also provides a total body imaging that may identify other metastases. However, PET or PET/CT is not reliable for identifying brain metastasis and a brain imaging study (CT or preferentially MRI) must be performed, particularly in cases of adrenal metastasis from lung cancer. If the primary cancer was fluorodeoxyglucose (FDG)-avid, the identification of benign characteristics on the PET/CT is sufficient to exclude adrenal metastasis. If the primary cancer was not FDG-avid, an adrenal biopsy may be needed if the CT characteristics do not provide an unequivocal diagnosis of adenoma. We do not consider that MRI is superior to CT and recommend it should only be used when CT studies cannot be performed (e.g., pregnant woman). Percutaneous biopsy Rationale Adrenal biopsy is of limited diagnostic value for an incidentally discovered adrenal mass [3, 54, 55]. However, in patients with an extra-adrenal malignancy CT-guided (or US-guided) adrenal biopsy is an important diagnostic tool. If negative, cytological evidence of adrenal tissue precludes metastatic adrenal malignancy making further evaluation unnecessary, reducing patient anxiety and avoiding unnecessary surgery. If positive for malignancy, it facilitates therapeutic planning in patients with no evidence of other metastases. Langenbecks Arch Surg (2012) 397:179–194 Usefulness Ex vivo studies with core biopsies of the adrenal gland have a positive predictive value of 100% and a negative predictive value of 92% for the diagnosis of malignancy [56]. The actual performance of adrenal biopsy in clinical practice is probably much lower. In some series, the sensitivity for metastatic adrenal disease is as high as 80% [57] and in others as low as 57% [58]. Its true yield is difficult to assess due to limited data, inconsistencies in series that mix biopsies of incidentaloma with those of potential metastasis, pooling results from core biopsy and FNA, and a lack of appropriate follow-up. Table 1 summarises the results from four relatively large series that address the accuracy of biopsy. Common findings in these series include a high overall accuracy, the virtual absence of false-positive results and a uniformly better performance of biopsy in detecting metastasis from lung cancer. However, data compiled by the National Institutes of Health revealed that in some centres, 75% of adrenal lesions found in patients with a known extra-adrenal malignancy are metastatic [59]. This high pretest probability certainly improves the biopsy accuracy in this population. CT-guided FNA may be helpful in the diagnostic evaluation of patients with a history of cancer (particularly lung, breast, and kidney), no other signs of metastases, and an inconclusive image evaluation [59]. Complications Complication rates range from 3% to 13%, although most are mild and self-limiting. Complications include adrenal haematoma, abdominal pain, haematuria, pancreatitis, pneumothorax, formation of a retroperitoneal abscess, and tumour recurrence along the needle track. Postbiopsy haemorrhage is more frequent after core biopsies than after FNA biopsies [26]. The prevalence of a pheochromocytoma in patients with a known malignancy and adrenal mass is 5–9% although in one study, a prevalence of 25% was found [60]. There are some reports of adrenal biopsies performed in patients with a pheochromocytoma without complications, but it is imperative to exclude adrenal medullary hyperfunction prior to biopsy in order to avoid haemodynamic and vascular complications, such as severe hypertension, myocardial infarction, or cerebrovascular events. Modalities Surgical treatment There are currently two options: percutaneous fine-needle aspiration (FNA) biopsy and core biopsy. Core biopsy obtains cylinders of approximately 1 mm in diameter and 0.8–2.0 cm long and can be performed using a manual or automated biopsy gun [56]. Indications Surgical resection of metastatic lesions of the adrenal gland were performed more than 30 years ago mainly for breast cancer treatment. In 1982, Twomey et al. [61] reported two Langenbecks Arch Surg (2012) 397:179–194 185 Table 1 Utility of adrenal biopsy in the diagnosis of adrenal metastasis in retrospective series Authors Year N Accuracya Sensitivity Specificity PPV NPV Notes Welch [78] Harisinghani [108] Paulsen [109] Mazzaglia [54] 1994 2002 2004 2009 277 225 50 127b 90% –c 94% –c 81% –c 94% 99% –c 90% 99% –c 97% 80% 100% 82% Majority of lung cancer NSCLC and renal cancer had the highest yield Majority of lung cancer Pooled FNA and C-B FNA fine needle aspiration biopsy, C-B core biopsy a Overall accuracy b Out of 163 biopsies including incidentalomas c Insufficient data to calculate patients who had a disease-free survival of 6 and 14 years after resection of isolated adrenal metastasis from large-cell lung cancer. Surgical treatment of adrenal metastasis has become an accepted therapeutic procedure following the study of Luketich and Burt [62] that demonstrated that resection of adrenal metastasis from nonsmall cell lung cancer provided significantly longer survival compared with a conservative approach. Patients undergoing surgical resection survived 30 months (on average) compared to survival rates of 6–8 months for patients from a historical cohort without resection [63]. Since then, numerous studies have reported improved survival rates after resection of solitary adrenal metastases for various types of primary tumours (Tables 2, 3, 4, 5, and 6). However, adrenalectomy in a cancer patient is still regarded as a therapeutic dilemma because there is no level Table 2 Published series of adrenalectomy for metastatic disease from various origins Author Year N Max survival Median survival % Long-term Primary type(s) Observations (months) (months) survivorsa Watatani [110] Lo [74] Kim [72] Heniford [75] 1993 1996 1998 1999 3 52 37 11 12 107 108 19 7 13 21 NR 60% 15%(b) 24% NR Colorectal Various Various Various Kebebew [58] Lam [16] Sarela [64] Miccoli [57] Sebag [71] Castillo [5] Okabe [111] 2002 2002 2003 2004 2006 2007 2007 17 21 6 16 16 22 7 84 75 62 108 68 64 54 40(c) 8 28 39(c) 23 26 23 NR NR 30% NR 33% Popescu [112] 2007 4 43 28.3(c) 0% Strong [68] 2007 94 126 29 30% Various Various Various Various Various Various Hepatocellular carcinoma Hepatocellular carcinoma Various Silvio-Estaba [113] 2007 13 108 2009 31 70 Marangos [63] de Haas [79] 2009 10 29 39.7 29 23 17% 18% 32% Various Various Colorectal Fumagalli [114] Muth [65] 24(c) 23 20%(d) 20% Oesophageal Various 2010 5 50 2010 30 120 NR NR not reported a More than 60 months b Eight patients censored at 36 months; pooled curative and palliative resections c Estimated mean survival after adrenalectomy d Estimated survival at 3 years, limited by follow-up All laparoscopic All laparoscopic Compares open and laparoscopy. Includes some of the Kim et al. and Sarela et al. series. Scandinavian multicentre study All with previous resection(s) of colorectal liver metastases Oesophago-gastric junction adenocarcinoma 186 Table 3 Effect on survival after adrenalectomy for metastasis of different factors Positive effect on survival • Origin renal cell carcinoma • DFI >12 months • Unique metastasectomy • Adrenalectomy for potential cure achieveda Positive or no apparent effect on survival • Tumour histology adenocarcinoma • Presentation time (metachronousb vs. synchronous) • Small size of metastasis No apparent effect on survival • Gender • Age • Surgical approach (open vs. laparoscopy) • Origin other primary Conflictingc results regarding effect on survival • Origin colorectal • Origin nonsmall cell lung carcinoma • Origin melanoma Negative effect on survival • Incomplete resection • Disseminated disease to other sites • Previous metastasectomy DFI disease-free interval, NSCLC nonsmall cell lung cancer a Primary resected, adrenal unique metastatic site, no border invasion in specimen b DFI >6 months c Positive in some studies, negative in others A evidence of producing a better outcome [64]. Surgeons should rely on the analysis of cumulative evidence gathered from the largest retrospective clinical series. In some studies, data is pooled from patients undergoing resection of adrenal metastases from all origins, whereas other studies focus on metastases from a single origin, notably the lung, kidney, or melanoma. Whether or not adrenalectomy affects the course of the disease cannot be easily assessed in a setting of multiple metastatic sites subjected to multimodal treatment strategies. Randomised studies have not been performed and there is a high bias in the selection of candidates for adrenalectomy when comparing operated and non-operated patients. However, the fact that adrenalectomy has been identified as an independent prognostic factor in series of metastases from multiple origins suggests that it has a beneficial effect on overall survival [65]. The identification of one or more resectable metastases in other places cannot be considered a contraindication for removing the adrenal metastases. In a multicentre Scandinavian study, good results were reported in several patients Langenbecks Arch Surg (2012) 397:179–194 where adrenalectomy was performed after multiple resections of metastases in different sites [63]. Factors to consider when selecting patients for adrenalectomy include: (1) whether control of extra-adrenal disease is achieved and the metastasis is isolated to the adrenal gland, (2) has biochemical evaluation been performed and appropriately addressed, (3) has the patient either an adrenal image highly suggestive of metastasis or a biopsy-proven adrenal metastasis that appears resectable on imaging studies, and (4) whether the patient’s performance status warrants a surgical approach [6, 58, 66–70]. In the opinion of several specialised groups, synchronous metastasis, short DFI, or other metastatic sites accessible to complete treatment should not be an exclusion criterion for surgical treatment [64, 71]. In some series of patients where pain was the major complaint, adrenalectomy proved successful in relieving the pain, although survival was very poor [5, 72–74]. Prognosis The patient with a solitary metastasis to any solid organ can benefit from excision, with a 5-year survival rate approaching 20–45% [62, 75, 76]. As over 25% of patients achieve a 5-year disease-free survival, adrenalectomy should be offered to patients with isolated adrenal metastasis [7]. Notably, a small subgroup of patients will achieve prolonged survival after adrenalectomy [64]. The Memorial Sloan Kettering Cancer Centre (MSKCC) published a study of 37 patients in 1998 [72] with a 5-year actuarial survival rate of 24%. In 2003, it was updated to 41 patients and the survival rate improved to 29% [64]. The last update brought the total to 94 patients and the survival rate again improved to 31% (37% at 2 years and 17% at 8 years) [68]. This is currently the largest series published and includes 31 patients operated laparoscopically. Paul et al. [77], in a large compilation study of 77 patients published in different series, reported encouraging results that showed a median survival of 23 months and 5-year survival rates between 20% and 45% [77]. Other groups have also published similar impressive survival results based on their experiences with adrenalectomy for metastases from different origins. In the majority of these mixed-case series, the median survival rate ranges between 20 and 30 months, and between 10% and 30% of patients are alive 5 years after adrenalectomy [5, 6, 58, 65, 71, 78] (Table 2). Prognostic factors Regarding tumour histology, patients with adrenal metastasis due to adenocarcinoma have a significantly improved survival rate compared to patients with other histological Langenbecks Arch Surg (2012) 397:179–194 187 Table 4 Selected series with five or more adrenalectomies performed for adrenal metastases from NSCLC Author Year N Max survival (months) Mean survival (months) % Long-terma survivors Notes Kirch [115] Higashiyama [116] Ayabe [76] Luketich [62] Porte [117] Wade [118] Beitler [21] Bretcha-Boix [23] Porte [67] Lucchi [119] Pfannschmidt [84] Mercier [85] Itou [82] 1993 1994 1995 1996 1998 1998 1998 2000 2001 2005 2005 2005 2006 12 5 12 8 11 47 32 5 43 10 11 23 6 183 40 168 61 66 86 92 58 72 80 70 110 36 36 9 47 31 6 20 24 34 11 31 12.6 13 24 25% NR NR 20% 9% 9% 30% 20% 15% 10% 10% 18% 16% Highly selected. Long DFI Comparison of adrenalectomy with palliative therapy Pooled analysis from 3 small series. Compares with non-adrenalectomised patients. Strong [68] 2007 29 127 28.6 22% Extracted from large multiorigin series. Compares laparoscopic and open access 5-year survival rate of 13%. Pooled analysis from 11 series. Multicentre retrospective. Does not include previous series. Reviews also published data from 104 additional patients. NSCLC nonsmall cell lung cancer, NR not reported, DFI disease-free interval a More than 60 months cell types [64, 65, 74]. Even when patients with potentially curative resection are considered as a separate group, the survival advantage for adenocarcinoma persists [65]. The reported effect of the primary tumour site on survival is controversial. The few series that specifically assess this issue suffer from significant study heterogeneity with varied chemotherapy, radiotherapy, and supportive treatment modalities. In a recent and detailed series covering different tumour types, patients with colorectal cancer had the most favourable outcome, whilst the survival rate was lowest for patients with nonsmall cell lung cancer and malignant melanoma [65]. Other authors however analysed a group of patients with previously resected colorectal liver metastases and concluded that adrenalectomy for metastases was not warranted given the poor survival prognosis [79]. Metastasis size does not appear to have any influence on survival. There was no significant difference in overall survival when comparing patients with small (<6 cm) and large (≥6 cm) adrenal tumours [63]. Several authors have tried to demonstrate that larger metastases carry a poorer prognosis [63, 64, 72, 76, 77], but only the review of Strong et al. associated metastases greater than 45 mm with a significantly poorer prognosis [68]. DFI has been defined as the time interval between primary surgery and detection of the adrenal metastasis, usually without taking into account other (resected) metastasis. Table 5 Selected published series of adrenal metastasectomy from renal cell carcinoma Author Year N Max survival (months) Median survival (months) % Long-term survivorsa Notes Plawner [120] 1991 14 172 63 29% Shalev [89] Lau [86] 1995 2003 11 11 120 48 20% Siemer [121] Antonelli [88] 2004 2006 56 48 120 142 20 99 19.6% 24% Bahrami [87] 2009 19 180 NR 25% With 7 patients pooled from literature. Mixed synchronous and metachronous adrenalectomy Out of 285 adrenalectomies during 299 radical nephrectomies Adrenal metastases contralateral to the renal cancer. Includes a review of 57 similar cases Out of 1,010 nephrectomies with adrenalectomy 875 removed en bloc during nephrectomy. Only 29 contralateral to the initial renal carcinoma Out of 550 radical nephrectomies. 15 adrenal involvement by contiguous spread not included NR not reported a More than 60 months 188 Langenbecks Arch Surg (2012) 397:179–194 Table 6 Selected published series of adrenal metastasectomy from melanoma Author Year N Max survival Median survival (months) % Disease-free patients Survival in disease free patients (months) Observations Branum [24] 1991 10 132 NR 80% 59 Out of a series of 28 melanoma metastatic to the adrenal gland Haigh [80] Collinson [73] 1999 2008 27 23 61 155 9.3 16 67% 57% 25.7 50 Mitterndorf [91] 2008 22 48 6.4 91% 20.7 Two cases of spontaneous regression of distant metastases after adrenalectomy NR not reported DFI can be considered a surrogate marker for both the aggressiveness of the tumour and the efficacy of medical treatment. As in other resectable metastases, it seems that a long DFI may indicate a favourable prognosis. In the initial MSKCC reports of metachronous tumours, patients with DFI >6 months had a better prognosis than those with DFI<6 months, which is consistent with data reported by others [64, 72, 77]. However, this association could no longer be confirmed in the latest update of MSKK [68] nor in series from other specialised units [67, 71, 74]. A Scandinavian study with a fair proportion of colorectal origins, found no significant difference in survival between synchronous and metachronous metastases [63]. Nevertheless, when a strict definition of DFI was used (the time when the patient was tumour-free prior to the recognition of adrenal metastasis and DFI >12 months), DFI was a prognostic factor clearly related to a more favourable outcome in patients with metachronous metastasis [65]. As may be expected, when completeness of the resection is assessed, this variable is strongly associated with an improved prognosis [64, 77, 80]. Specific cases Nonsmall cell lung cancer Adrenal metastasis from lung cancer usually implies that the disease has spread outside the chest and is generally considered incurable. However, patients with isolated adrenal metastases from nonsmall cell lung cancer (NSCLC) have a favourable survival compared to those with isolated distant metastases to other sites [81]. Additionally, as the results summarised in Table 4 suggest, a subset of patients with isolated adrenal metastases may achieve long-term survival rates after surgical resection of the adrenal gland [21]. In a retrospective review of 104 cases of adrenalectomy for metastasis of NSCLC, Itou et al. [82] showed a mean survival of 24 months and a 5-year survival rate of 31%. A recent review of adrenalectomy for isolated metastases in a large series of patients with NSCLC (n06,577) treated at the MD Anderson Cancer Center supports the rationale for adrenalectomy in selected NSCLC patients with adrenal metastases [83]. A DFI >6 months has been consistently identified as a favourable prognostic factor in NSCLC [65, 84, 85]. In a large French study, all patients with a DFI interval <6 months died within 2 years after resection of the adrenal gland, whereas 38% of the patients with a DFI >6 months were alive 5 years after adrenalectomy [85]. In a study of adrenal metastases of NSCLC carried out by Mercier et al., metachronous tumours were associated with a better prognosis [85]. Previous, concurrent, or metachronous brain metastases had been removed in some of these patients with satisfactory immediate results [81], and therefore resection of brain metastasis is not considered a contraindication for subsequent adrenalectomy in patients with NSCLC. Renal cancer The behaviour of renal cell carcinoma (RCC) is unpredictable; metastasis to various organs may be found synchronously with the primary tumour or many years after treating the primary RCC [86]. Renal cancer can spread to either ipsilateral or contralateral adrenal glands. Adrenal involvement in the setting of RCC has important prognostic implications. Ipsilateral adrenal invasion by direct extension is classified as pT3a by the American Joint Committee on Cancer staging system, whereas haematogenous dissemination is defined as stage IV. In general, the presence of adrenal metastasis in patients with RCC is associated with poor outcomes [87]. The extended practice of routine simultaneous resection of the ipsilateral adrenal gland even if it is not infiltrated has been questioned. In two studies with more than 1,000 patients where adrenalectomy was routinely performed, adrenal metastases were detected in 1.4% and 2.7% of patients, respectively [88, 89]. Therefore routine ipsilateral adrenalectomy is not recommended if the adrenal glands appear normal at the time of surgery and the tumour is smaller than 4 cm on the CT scan [90]. Langenbecks Arch Surg (2012) 397:179–194 189 Melanoma Although in autopsy-based series about 50% of patients with advanced melanoma were found to harbour adrenal metastases, ante-mortem diagnosis of adrenal metastases from melanoma is rarely established [80]. Twenty years ago, there was some evidence that surgical resection of asymptomatic, small, and solitary adrenal metastasis could be potentially curative in patients with melanoma [24]. Two important and recent series assessing resection of isolated adrenal metastasis from melanoma have shown that adrenalectomy can provide excellent palliation of symptoms and, in a selected subset of patients, prolonged survival [73, 91]. There were two patients with unexpected tumour resolution after adrenalectomy, perhaps related to the presence of high-affinity glucocorticoid receptors in the melanoma cells [73]. Mittendorf et al. analysed the prognostic factors and indications of adrenalectomy in a large series of patients from the MD Anderson Cancer Center. Disease circumscribed to the adrenal gland and normal LDH levels were the most important outcome predictors. Additional factors that favour surgical resection include symptomatic metastasis, a DFI ≥1 year, resectable extra-adrenal disease and partial response to preoperative systemic therapy [91]. Patients with unresectable extra-adrenal disease achieved no survival benefit from adrenalectomy [80]. Open surgery or laparoscopy The key factors for a successful adrenalectomy are adequate surgical margins and avoidance of tumour fracture to prevent local recurrence. This can be carried out by open or laparoscopic approach. Laparoscopic adrenalectomy has become the standard treatment for benign adrenal tumours. Compared with open adrenalectomy, laparoscopic adrenalectomy is associated with significantly less postoperative pain and morbidity, shorter hospital stay, and convalescence as well as smaller scars. The postoperative benefits of laparoscopic adrenalectomy are well-established, but questions remain regarding long-term oncologic outcomes when used for malignant lesions [4]. Traditionally, open adrenalectomy was the preferred option for patients with adrenal metastasis. The first report of laparoscopic adrenalectomy for malignancy was published in 1999 [75], but the procedure has been relatively slow to gain acceptance. Because solitary adrenal metastases from an extra-adrenal primary neoplasm are usually small and confined to the adrenal gland, the laparoscopic approach has considerable appeal for these cases [92]. The critical issue is whether laparoscopic adrenalectomy can be considered equivalent to open adrenalectomy from an oncological point of view, in terms of recurrence rates and survival time. Proper patient selection for the laparoscopy versus open approach remains paramount in deciding the best treatment [1]. Ensuring wide surgical margins with en bloc excision of peri-adrenal fat is an absolute requirement [92]. Although some initial studies suggested than laparoscopy was not appropriate due to its high conversion rate to open surgery, refinements in preoperative diagnosis and operative technique have eliminated these initial concerns [66]. Some authors have reported acceptable oncologic outcomes after resection of metastatic lesions of the adrenal gland for very small series of patients or for patients with some types of primary tumours, such as NSCLC or RCC [66, 74, 77, 85]. Others have shown promising results in series pooling different primary tumours [71, 93]. Adler et al. [4] reported a nonrandomized retrospective comparison between nine open and eight laparoscopic adrenalectomies with a follow-up of 97 months. The laparoscopic group had a similar median survival (17 vs. 19 months), less blood loss, shorter postoperative stay, and no port-site metastasis, although a nonsignificant, but somewhat shorter, 5-year survival. Strong et al. [68] retrospectively analysed the Table 7 Series with direct comparison between open and laparoscopic approach to adrenalectomy for adrenal metastases Authors Sarela [64] Adler [4] Strong [68] Muth [65] Year 2003 2007 2007 2010 Months of follow-up max (mean) 69 (16) 97 (13) 125 (42) 35 (16) N 41 17 94b 30 Median Survival (months) 5-Year survival LAP OPEN LAP NR 19 30 23 28 17 29 29%a 34% 54% 25% 33% 22.5%a NR not reported a Pooled calculation without specific group comparison b Some patients included in previous series by Sarela et al. Notes OPEN Tumours by Lap significantly smaller than by Open. Non-significant differences in 5 year survival. Nonsignificant differences in 5 year survival. 190 results of 31 laparoscopic and 63 open adrenalectomies. There were no differences in the median survival (approximately 30 months) or positive margin rate (22% laparoscopy vs. 29% open). As expected, the laparoscopic group benefited from lower blood loss, operative time, hospital stay, and complication rates. The majority of authors report no port-site metastases or locoregional recurrences after laparoscopic adrenalectomy for metastatic tumours even after a long-term follow-up [94, 95] (Table 7). The case for open surgery is stronger when preoperative imaging suggests local invasion. Other indications for open surgery are large metastasis (>9 cm), caval thrombus or significant lymphadenopathy. Relative contraindications for the laparoscopic approach include significant adhesions from prior surgery, morbid obesity, uncorrected coagulopathy, and severe cardiopulmonary disease that precludes the hypercapnia that is associated with pneumoperitoneum [1]. Nonsurgical modalities Langenbecks Arch Surg (2012) 397:179–194 control with very limited toxicity [100]. In a series of 30 patients in which radiotherapy was indicated for nonresectable adrenal metastasis, the median overall survival was 19 months. Although the procedure was well tolerated, most patients developed widespread metastases shortly after treatment [101]. Recent studies have focused on the potential curative role of stereotactic body radiation therapy in limited metastatic disease [100]. For adrenal metastasis from lung cancer, radiotherapy has been reported to achieve a 5-year survival rate of 22%, and even 56% in a reduced group of metachronous metastasis [102]. Other ablative techniques Alternative ablation techniques, such as ethanol injection [103], ultrasound-guided percutaneous microwave [104], CT-guided laser-induced interstitial thermotherapy [105], cryoablation [1], or radiofrequency plus chemoembolization combined therapy [106] have been sporadically reported but experience is too limited to assess its value. Radiofrequency ablation Numerous clinical studies have shown that radiofrequency energy is effective, safe, and technically feasible for ablation of primary and metastatic tissue [96]. With the introduction of new emission units and electrodes, percutaneous radiofrequency therapy is emerging as a treatment modality to ablate neoplasms in a variety of tissues, including liver, spleen, lung, bone, breast, prostate, and kidney [1]. Percutaneous, image-guided RF ablation is usually a welltolerated procedure and can be performed under sedation or general anaesthesia. It may present complications such as bleeding, infection, hypertensive crisis, pneumothorax, and nontargeted thermal damage. Monitoring carried out by CT or magnetic resonance imaging with contrast injection will show an absence of enhancement by the tumour [97]. Over the last decade, there have been several reports of patients with unresectable adrenal metastases or poor operative risk treated with radiofrequency ablation without major complications and acceptable local control [97–99]. One of the largest studies reported the successful treatment of 11 adrenal metastases, six isolated to the adrenal gland, successfully controlled with chemotherapy, radiation therapy, and/or surgical resection. The average survival time was 8 months after the adrenal tumour treatment (range, 3– 16 months). There were no patients with recurrent tumour at the adrenal bed indicating effective local control [96]. Stereotactic body radiotherapy Radiation therapy has traditionally played a palliative role in the treatment of adrenal metastases, achieving excellent pain Conclusions After presenting the results of this review at the European Surgery of Endocrine Surgeons 2011 Workshop (May 12– 14, Lyon, France), a set of conclusions were agreed upon. These conclusions are presented here, followed by the evidence level and recommendation grade [107] 1. Patients are better managed by a multidisciplinary team (5;D). 2. PET/CT is the test of choice in patients with suspected adrenal metastasis. If PET/CT is not available or inconclusive, a CT scan with washout assessment can be used (2b,3b;C). 3. Adrenal biopsy can be reserved for lesions without a conclusive imaging diagnostic (3b;C). 4. Complete hormonal evaluation must be performed (5;D). 5. If malignancy is reliably ruled out, the incidentaloma should be managed as for noncancer patients (5;D). 6. Consider a patient with suspected adrenal metastasis for adrenalectomy when (4;C): (a) Control of extra-adrenal disease has been achieved, or a definite plan for control is in place. (b) Metastasis is isolated to the adrenal gland(s). (c) Adrenal image is highly suggestive of metastasis or proven by biopsy. (d) The adrenal metastasis is confined to the adrenal gland as assessed by a recent image (1 month). (e) Performance status warrants a surgical procedure. Langenbecks Arch Surg (2012) 397:179–194 7. The laparoscopy (or retroperitoneoscopy) is a feasible and oncologically safe approach in properly selected patients (2b;B). Acknowledgements We thank Marta Pulido, MD, and Mr. Philip Little for editing the manuscript and editorial assistance. Conflicts of interest None References 1. Uberoi J, Munver R (2009) Surgical management of metastases to the adrenal gland: open, laparoscopic, and ablative approaches. Curr Urol Rep 10(1):67–72 2. 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