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Best Practice & Research Clinical Endocrinology & Metabolism
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Clinical Endocrinology & Metabolism
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Surgery for adrenocortical carcinoma: When and how?
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Tiffany J. Sinclair, MD, Resident in General Surgery ª, Andrea Gillis, MD, Resident in General Surgery b,
Wilson M. Alobuia, MD, Resident in General Surgery ª, Hannah Wild, BS, Medical Student ª,
Electron Kebebew, MD, Professor of Surgery, Chief, Division of General Surgery a,
ª Division of General Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA
b Division of General Surgery, Department of Surgery, Albany Medical College, Albany, NY, USA
ARTICLE INFO
Article history: Available online 3 March 2020
Keywords:
adrenal cancer surgery adrenalectomy resectability tumor margins CT scan
Adrenocortical carcinoma (ACC) is a rare malignancy that is frequently asymptomatic at presentation, yet has a high rate of metastatic disease at the time of diagnosis. Prognosis is overall poor, particularly with cortisol-producing tumors. While the treatment of ACC is guided by stage of disease, complete surgical resection is the most important step in the management of pa- tients with primary, recurrent, or metastatic ACC. Triphasic chest, abdomen, and pelvis computer tomography (CT) scans and 18F flourodeoxyglucose positron emission tomography CT scanning are essential for accurate staging; moreover, MRI may be helpful to identify liver metastasis and evaluate the involvement of adjacent organs for operative planning. Surgical resection with negative margins is the single most important prognostic factor for survival in patients with ACC. To achieve the highest rate of R0 resection, open adrenalectomy is the gold standard surgical approach for confirmed or highly suspected ACC. It is extremely important that the tumor capsule is not ruptured, regardless of the surgical approach used. The best post-operative outcomes (complications
Abbreviations: AOR, Adjusted odds ratio; HU, Hounsfield units; OS, Overall survival; LAD, Lymphadenectomy.
* Corresponding author. 300 Pasteur Drive, H3642, Stanford, CA, 94305, USA. E-mail address: kebebew@stanford.edu (E. Kebebew).
and oncologic) are achieved by high-volume surgeons practicing at high-volume centers.
Introduction
Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated incidence of 0.5-2 cases per million persons annually [1,2]. Most cases are sporadic, while fewer than 10% appear in association with hereditary syndromes such as Li-Fraumeni, Beckwith-Weidemann, and, less commonly, multiple endocrine neoplasia (MEN) type 1, Lynch syndrome, and familial adenomatous polyposis [3-5]. A disproportionately high incidence of ACC recently observed among a pediatric population in southern Brazil is thought to be due to a founder mutation (R337H) in TP53, the tumor suppressor gene linked with Li-Fraumeni syndrome [6,7]. ACC affects women more commonly than men, with a female-to- male ratio of 1.25-1.5:1 [8]. It has been hypothesized that this female predominance is related to the role of estrogen in tumorigenesis, mediated by the action of 17b-estradiol on adrenocortical cells [9]. The average age at presentation is in the fourth and fifth decades of life [2,10-12]. Although risk factors for ACC are not well-understood, a recent study identified several possible relationships. An increased risk of ACC was associated with a family history of cancer in both men and women (AOR 2.8), and with tobacco use among men (AOR 1.8) but not women; a reduced risk of ACC was associated with alcohol consumption in men (AOR 0.2) but not women [13].
The prognosis for ACC is overall poor, especially in cases where the disease is advanced at the time of diagnosis. Median overall survival (OS) has been estimated at 3.21 years from diagnosis [10]. The European Network for the Study of Adrenal Tumors (ENSAT) classification is widely used to define ACC stage. Stage I disease is defined as tumor size less than or equal to 5 cm, with a reported five-year survival rate of 82%. Stage II disease is defined as tumor size greater than 5 cm (58% five-year sur- vival), Stage III as any tumor size with at least one positive lymph node or infiltration of surrounding structures including tumor thrombus in the inferior vena cava or renal vein (55% five-year survival), and Stage IV is defined by the presence of metastatic disease, with a particularly poor prognosis (five- year survival of 18%) [14,15]. A recent case series reported more favorable five-year survival for Stage I, II, and III disease (100%, 93%, and 60% respectively), likely due to a high number of patients undergoing surgery and adjuvant therapy, but a similarly poor prognosis for Stage IV ACC (11%) [16].
Although the clinical presentation of ACC is variable, almost 80% of patients are asymptomatic at the time of diagnosis and the lesion is found incidentally on imaging [16]. Symptomatic patients may present with complaints related to hormonal overproduction from functional tumors (40-60%), abdominal discomfort or pain secondary to the mass effect (~33%), or constitutional symptoms of malignancy such as anorexia and cachexia [11,12,17]. ACC is frequently advanced at the time of diag- nosis, with locoregional disease evident in 10-26% of patients on diagnostic imaging and nearly 70% of patients at autopsy. Distant metastases are found at presentation in almost 22% of patients, most frequently involving the lung (~45%), liver (~42%), and less commonly bone [8,18-20].
The most common hormone secreted by functional ACCs is cortisol (50-80%), which may lead to ACTH-independent Cushing syndrome with symptoms including facial plethora, proximal muscle weakness, diabetes mellitus, easy bruising, and weight gain, although in rapidly progressive cases the latter may be masked by the catabolic effects of malignancy [11,21]. Adrenal androgen secretion is produced in 40-60% of functional ACCs, causing male-pattern baldness, hirsutism, virilization, and menstrual abnormalities in women [11]. Aldosterone secretion is rare, though mineralocorticoid excess may result from the glucocorticoid-mediated activation of mineralocorticoid receptors in patients with hypercortisolism [22,23]. Simultaneous secretion of cortisol and androgens occurs in approximately 50% of cases, and is a hallmark of ACC [18,21].
Functional tumors, in particular those that produce cortisol, are associated with worse outcomes in ACC, including shorter OS and recurrence-free survival, as well as increased perioperative morbidity [1,9,24,25]. A systematic review and meta-analysis assessing the association between hormone
secretion and survival in ACC found a higher mortality risk (RR 1.71) and recurrence risk (RR 1.43) in cortisol- but not androgen-producing ACCs [26]. It remains unclear as to whether this is due to the systemic effects of cortisol overproduction, or whether cortisol-producing tumors represent a more aggressive subset of ACC.
Limited research has been devoted to patterns in the treatment utilization and treatment practice in the management of ACC. A 2017 analysis of the American College of Surgeons National Cancer Database (NCDB) investigated the association of demographic and socioeconomic characteristics with access to surgical care and OS in patients with ACC [27]. Though only age greater than 56 years was found to be significantly associated with a worse prognosis, patients who were male, African-American, insured by a government insurer (i.e. Medicare, Medicaid), or treated at community cancer centers were signifi- cantly less likely to undergo surgical resection, suggesting concerning disparities in access to surgical care. A previous analysis of the NCDB similarly found age greater than 55 years to be the only socio- economic or demographic factor associated with worse survival in ACC [19]. In this study, the majority (45.7%) of patients received care at community hospitals, followed by academic centers (30.6%), NCI- designated cancer centers (15.5%), and VA hospitals (1.2%). Studies from Europe have shown that designated or coordinated care at ACC designated centers may result in better OS [28,29].
Indications and preoperative evaluation
The treatment approach to ACC is predominantly guided by disease stage at the time of diagnosis. Surgical resection is the definitive treatment for Stage I-III ACC, including tumors with local invasion into surrounding organs and vena cava involvement [21,30,31]. Stage III tumors deemed unresectable at presentation may become resectable after a partial response to neoadjuvant therapy [30]. The role of surgery in Stage IV metastatic disease is highly individualized, and will be discussed in greater detail later in this review.
Imaging is the cornerstone of ACC diagnosis, and radiographic features of ACC have been extensively described in the literature. Benign adrenal adenomas are characterized by a homogenous appearance, size <4 cm, and <10 Hounsfield Units (HU) on unenhanced CT (Fig. 1) [32]. In contrast, ACCs typically have a heterogeneous appearance, size >6 cm, and >10 HU, with a median HU as high as 34 (Fig. 1) [33]. Using size threshold alone, a maximum dimension greater than 6 cm has a sensitivity and specificity of 91% and 80%, respectively, for ACC [18]. In most cohorts, only 3% of ACC are less than 4 cm in diameter at the time of detection, with a mean diameter of 12 cm in several large studies [18,34]. ACCs frequently have irregular borders, and contain areas of necrosis, hemorrhage, and calcification. Finally, they often demonstrate involvement of surrounding structures such as adjacent organs, i.e. the kidney, distal pancreas, spleen, liver, diaphragm, lymph nodes, as well as the vasculature, i.e. the adrenal veins, renal veins, and inferior vena cava (IVC) (Fig. 2) [18,20,35].
A
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Overall, contrast-enhanced CT is capable of ruling out benign lesions with a sensitivity and speci- ficity of over 90%, and is thus an appropriate first method to diagnose and stage disease [20]. On MRI, ACC typically demonstrates hypo- or iso-intensity to the liver on T1-weighted images and high signal intensity on T2-weighted images, though heterogeneity may be present due to areas of focal hemor- rhage, necrosis, and intracytoplasmic fat (Fig. 3) [36,37]. Using in-and out-of-phase sequencing, MRI has a sensitivity of 85-100% and specificity of 92-100% for identifying malignant adrenal lesions [31]. If vascular involvement is suspected, gadolinium-enhanced MRI must be obtained, as MR angiography is superior to CT in the diagnosis of venous tumor thrombus or venous invasion [11,20].
(18F)fluorodeoxyglucose (FDG) PET-CT has an important role in the radiographic assessment of suspected ACC, and may be used to support the diagnosis, clarify disease stage, or detect distant metastases. ACCs typically have intense uptake on FDG-PET, with high standardized uptake value (SUV) ratios (Fig. 4). While FDG PET-CT has 100% sensitivity and 88% specificity in identifying malignant adrenal lesions [38], it is unable to distinguish ACC from other lesions demonstrating high metabolic activity, such as metastases from another primary malignancy, pheochromocytoma, or certain benign conditions [11,39] (11C)metomidate (MTO) is a recently-developed tracer that is highly specific for cells of adrenocortical origin, with targeted binding to 11b-hydroxlyase and aldosterone synthase [23,37]. Investigations into the use of this marker in the pre-operative evaluation of ACC are ongoing.
The European Society of Endocrine Surgeons and the European Network for the Study of Adrenal Tumors published summary guidelines in 2017 recommending preoperative imaging including CT chest-abdomen-pelvis and (18F)fluorodeoxyglucose (FDG) PET-CT within 6 weeks prior to planned adrenalectomy for suspected ACC. Additionally, gadolinium-enhanced MRI is recommended for pa- tients in whom vascular invasion or hepatic metastasis is suspected [20].
While a complete preoperative endocrine work-up is necessary for all patients with suspected ACC to establish the secretory profile of the tumor and identify potential tumor markers for detection of recurrence after resection, several factors are of particular importance with respect to surgical plan- ning. Urinary or plasma normetanephrine and metanephrine must be checked to rule out pheochro- mocytoma prior to surgery and avoid potential intra-operative complications [20,21]. Cortisol excess should be measured even in patients without Cushingoid features due to the life-threatening risk of post-operative adrenal insufficiency in cases of cortisol-secreting ACCs [21]. Aldosterone secreting tumors precipitate significant hypertension and hypokalemia, derangements which should be managed expectantly in the pre- and perioperative period.
Preoperative biopsy should not be performed in the evaluation of suspected ACC if the disease is deemed surgically resectable. Biopsy has a low sensitivity and specificity for the diagnosis of ACC, with
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=
a high false-negative rate and a reported misclassification rate of up to 13% [40]. A negative biopsy is, therefore, unlikely to change the decision to proceed with surgical resection in the setting of adrenal lesions that are suspicious for malignancy based on size or radiographic criteria. Moreover, the pro- cedure is accompanied by risks, including rupture of the tumor capsule, seeding of the needle tract, and complications of the procedure itself such as hemorrhage or pneumothorax [41-45]. An analysis of the NCDB data found that preoperative biopsy was performed more frequently outside of academic cancer centers (OR 1.36), and demonstrated no benefit for OS in ACC in patients who underwent adrenalec- tomy with negative margins [46]. Similarly, a retrospective review of ACC patients at a single institution found no benefit in recurrence-free or OS for patients who underwent biopsy, and further reported a complication rate of 11% [44]. Special circumstances in which a biopsy may be indicated include ruling
out adrenal metastasis from an extra-adrenal synchronous primary malignancy or attempting to establish a diagnosis of ACC for the purposes of guiding non-operative therapy in patients who are not surgical candidates [44,46].
Practice point
· Initial staging for ACC should include high resolution, contrast enhanced chest, abdomen and pelvic CT scan, MRI to define locoregional invasion or liver metastasis, and 18F FDG PET CT scan.
Goals of intervention
The goal of surgery in ACC is the complete removal of all disease with R0 resection, the achievement of microscopically negative margins. Technically, this requires en bloc resection of the tumor, including any involved organs, without disruption of the tumor capsule [47,48]. Complete surgical resection (R0) offers the best chance of cure or tumor free survival for stages I-III ACC with an OS of 32-48% at 5 years. Comparatively, the presence of any residual disease from either metastases or incomplete surgical resection (macroscopically/R2 positive margins) is associated with a median survival of <1 year [19,49-51].
The ability to achieve a complete surgical resection is highly dependent on the extent of the tumor, emphasizing the need for early diagnosis. Tumors localized to the adrenal gland are most likely to be resected in entirety without capsule violation [48]. Unfortunately, patients with ACC are often diag- nosed after the tumor has progressed extra-adrenally. Over 20% of patients are found to have evidence of metastatic disease at presentation [19]. Even those initially classified as stage I or II at diagnosis are upstaged during surgery approximately 30% of the time [52].
In cases of locally advanced ACC, aggressive surgery should be attempted if negative margins can be safely obtained. If involved, this may require en bloc resection of nearby solid organs such as the ipsilateral kidney, pancreas, or diaphragm. Large vessels, including the renal vein or inferior vena cava (IVC), may need to be resected en bloc with the specimen and later reconstructed. The tumor thrombus may extend into the IVC or right atrium (Fig. 5). Tumor thrombus embolectomy may require cross- clamping the IVC or utilizing a cardiac bypass technique with good oncologic outcomes [53]. Endo- vascular approaches to IVC thrombectomy may also result in the palliation of symptoms [54].
Surgical treatment of advanced disease involving disseminated tumor outside of the adrenal gland remains controversial. Outcomes are difficult to study given the paucity of cases and poor overall prognosis for these patients. There is limited retrospective data that suggests improved survival when full R0 resection is achieved at all sites [55]. Dy and colleagues studied 27 patients who underwent resection of single and multi-site metastatic ACC and reported a significantly better median OS with R0 resection versus R2 resection (28.6 vs 13.0 months, respectively) [56]. Adjuvant therapy likely plays an important role in these positive outcomes [56,57].
ACC carries a high risk of recurrence regardless of margin status and almost 75% of patients will experience recurrent disease by five years [51]. Nevertheless, ACC recurrences and metastases are likely best treated with surgery when feasible [50]. Hepatic metastases, one of the most common sites of recurrence, have been treated successfully with surgical resection, arterial chemoembolization, and radiofrequency, or cyroablation [58,59]. Goujeux and associates reviewed 28 patients who underwent surgical resection of hepatic ACC metastases, and while 100% of patients recurred, the five-year OS was only 40% [60].
Pulmonary ACC metastases that are reasonably accessible may be surgically removed, as well. Op den Winkel et al. described the outcomes of 56 pulmonary metastasectomies with a median survival of 50 months and a five-year survival of 24.5% [61]. Kemp and colleagues also reported similar results after 60 pulmonary metastasectomies, ranging from wedge resection to pneumonectomy, with a median survival of 40 months and five-year actuarial survival of 41% [62].
Liver displaced by tumor
Tumor
10 cm
Tumor thrombus IVC
Tumor
IVC
Kidney: displaced by tumor
Several positive prognostic factors are associated with improved outcomes after metastasectomy: disease-free interval from initial resection to metastatic recurrence >12 months, presence of solitary metastasis, and complete resection of recurrent disease [63,64]. Such patient-specific factors should be used for prognostication and to tailor individual therapy for recurrent disease. Patients with favorable prognostic factors could be considered for surgical metastasectomy, while patients with unfavorable disease characteristics may need to pursue less medical or ablative therapy [48].
Palliative surgical resection for ACC is considered when resection, without curative intent, offers the patient significant benefit over medical or supportive care alone. One benefit to reducing the tumor burden is to control the effects of excess steroid hormones produced by the majority of advanced ACCs when not responsive to adrenolytic therapy or anti-cortisol medications [65]. Palliative resection may allow for the initiation chemotherapy when patient symptomatology is more tolerable. Finally, surgical resection may be used as a method of palliation to control tumoral hemorrhage or locoregional mass effects [66]. In some instances, surgical resection of oligometastases is considered at some centers for a lesion that is significantly growing.
ACC in children is very rare. Individuals with inherited syndromes, however, including Li-Fraumeni, MEN type 1, Lynch syndrome, Beckwith-Wiedemann, and familial adenomatous polyposis are all at an
increased risk for developing ACC at a younger age [11,67]. The surgical treatment for children must be spearheaded by specialists, but mirrors the treatment of adults with ACC [68]. There are no specific guidelines for screening or prophylactic treatment in at-risk individuals. However, clinicians must be aware of these genetic associations and have a high clinical suspicion for malignancy and low threshold to investigate any abnormalities on imaging.
Practice point
· Palliative resection even in patients with Stage IV may be beneficial to control disease.
Research agenda
. The role of primary tumor or locoregional resection of ACC in a patient with Stage IV disease needs to be evaluated to determine if it impacts survival.
· Studies are needed to determine if metastasectomy is beneficial to patients with ACC.
Surgical approaches
As discussed, patients with potentially resectable disease should undergo aggressive en bloc sur- gical resection with negative margins (R0 resection), whenever possible. During dissection, care must be taken not to compromise tumor integrity or cause tumor rupture [51]. As such, enucleation and partial adrenalectomy is contraindicated in the management of ACC/suspected ACC [20]. Although aggressive surgical resection has been repeatedly shown to prolong OS in some patients, the appro- priate surgical technique has been debated for years. The adrenal glands’ deep retroperitoneal location, hypervascular attachments to adjacent organs, and fragile capsule require meticulous surgical tech- nique. Consequently, these factors also place ACC tumors at higher risk of rupture at the time of resection [31]. Surgery for ACC therefore requires a safe surgical approach that allows for both good exposure and atraumatic tumor manipulation and, most importantly, gives the patient the best oncologic outcome [69,70].
Open adrenalectomy
Open adrenalectomy remains the gold standard for resection in patients with ACC. Despite the advent and popularity of minimally invasive surgical techniques, the very important principle of achieving an R0 resection in ACC makes open adrenalectomy the preferred technique. Several studies have compared open with laparoscopic adrenalectomy and the results overwhelmingly show that open adrenalectomy is superior, allowing for more complete oncologic resection and improved surgical outcomes [71,72]. Due to significant risks associated with the use of other surgical techniques in ACC (discussed further below), the Society of Surgical Oncology (SSO), the European Society of Endocrine Surgeons (ESES), and the European Network for the Study of Adrenal Tumors (ENSAT) all strongly recommend the open approach as the gold standard of surgical care for confirmed or highly suspected ACC [20,73].
Minimally invasive adrenalectomy
Minimally invasive adrenalectomy has been recognized as the standard of care for the resection of benign adrenal tumors [74,75]. Conversely, the technique of laparoscopic adrenalectomy for malignant disease has remained a highly debated topic. Compared to open adrenalectomy, the laparoscopic
approach has been shown to be associated with less pain, shorter hospitalization and recovery, less operative blood loss, and fewer transfusions [76,77]. The use of laparoscopy in the management of malignant adrenal tumors has significant disadvantages, however. Although several series have re- ported good outcomes with the use of laparoscopic adrenalectomy in ACC [78-80], this technique has been associated with a high risk of adrenal capsular rupture leading to local recurrence and peritoneal carcinomatosis [81-84]. As a result, open adrenalectomy has become the preferred/standard technique for the resection of ACC, and is advocated by multiple professional associations and reported guidelines [20,73]. In rare cases, in patients with a tumor <6 cm without any evidence of local invasion, laparo- scopic adrenalectomy may be performed by an experienced surgeon, provided that all principles of oncologic surgery are followed, and that the procedure be converted to an open operation if increased risk of capsular disruption or local invasion is suspected [20,73]. Overall, the outcomes of laparoscopic adrenalectomy for ACC depend on disease stage, as well as surgeon expertise and volume. Several systematic reviews found laparoscopic surgery for localized ACC (T1-2) to be safe and effective [29,72,85], especially when performed by “expert surgeons” in “high-volume centers” but also emphasized that extensive tumors should be removed using an open surgical approach [29]. It is unclear, however, what constitutes an “expert surgeon” and a “high-volume center”.
Robotic and retroperitoneoscopic adrenalectomies have been safely performed and reported [86-88]. The use of these techniques in ACC, however, has not been specifically evaluated. These techniques have been used for larger tumors [89] with similar outcomes as laparoscopic adrenalec- tomy [90]. In general, the limiting factor to their popularity and use, especially for robotic adrenal- ectomy, remains the complex setup requirements and associated cost [91]. Compared to laparoscopic and open adrenalectomy, robotic adrenalectomy has been shown to shorten operative time and reduce postoperative pain [87].
Practice point
· Open resection to ensure negative margins and avoid tumor rupture are essential in patients with ACC undergoing operative intervention.
Research agenda
. If minimally invasive surgery for small ACC or suspected ACC is appropriate or leads to inferior oncologic outcomes is unclear and needs to be studied.
Outcomes after surgical treatment
Beyond early stage of disease and prompt diagnosis, complete surgical resection has been shown to be the most important prognostic factor for survival in patients with ACC [92-94]. This is true for patients with primary disease, as well as recurrent or metastatic disease [57,60,62,95]. Surgical resection is therefore the most essential part of management of patients with any stage ACC. To this end, nomograms to predict individual rates of recurrence-free and OS after curative resection of ACC have been reported [96]. Similar to other studies, large tumor size, positive nodal status, and R1 resection margin were associated with poorer OS. Adjuvant chemotherapy for recurrent or metastatic disease after radical resection of ACC has an unclear benefit with studies showing mixed results [57,97-99]. There is limited data surrounding postoperative radiation therapy in patients with ACC, but overall no survival benefit has been demonstrated [73].
Practice point
· RO resection (negative tumor margins) determines the risk of recurrent disease.
The role of lymphadenectomy in ACC
The use of prophylactic lymphadenectomy (LAD) in ACC is uncommon, and is usually reserved for patients with larger tumors or advanced disease [100,101]. The impact of LAD on survival after adre- nalectomy has been variable in the literature [100,102]. One study demonstrated that resection of at least five lymph nodes with the specimen was associated with a reduction in the risk of local recur- rence and improved oncologic outcomes [101]. Another multicenter study showed that LAD was independently associated with improved OS in patients who underwent margin-negative resection for localized ACC [103]. While generally considered to have unpredictable lymph node metastases, a recent study showed that metastatic lymphatic spread in ACC may be more extensive than previously thought [104]. Given these findings, more studies are needed to evaluate and understand the exact role and extent of LAD in the management of patients with ACC. Regardless of the impact of LAD on outcomes, lymph node dissection remains an important part of the accurate staging of ACC.
Practice point
· Therapeutic (removal of alterated lymphnode) (clinically suspicious based on imaging or intraoperative assessment) lymph node dissection should be performed in patients with ACC
Research agenda
. The role of prophylactic LAD should be studied in patients with ACC.
· What lymph node basins should have prophylactic LAD should be investigated in patients with ACC.
Perioperative considerations and complications
Both laparoscopic and open approaches to adrenalectomy are considered safe; however, little data exists about the specific complications associated with resection of adrenal malignancies, including ACC. Several large national studies published recently documented an overall complication rate of 11-18% for adrenalectomies, including both laparoscopic and open cases [105,106]. In a single-center series examining outcomes after surgical resection of ACC in 47 patients, a postoperative complication rate of 16% was reported, most of which were infectious [16]. While this rate is comparable to the published rate of complications for adrenalectomies overall, a study directly comparing postoperative outcomes after resection of benign vs. malignant adrenal tumors demonstrated higher rates of com- plications associated with malignant disease. Marcadis and colleagues reviewed 23,297 patients from the Nationwide Inpatient Sample database undergoing laparoscopic or open adrenalectomy for non- functional primary adrenal tumors and found that patients with malignant tumors had higher rates of intraoperative vascular and splenic injuries, as well as higher rates of postoperative complications including hematoma, adrenocortical insufficiency, venous thromboembolism, pneumothorax, shock, and cardiac complications compared to patients who underwent resection for benign disease [107]. Chylous ascites has also been described after radical resection of ACC with extensive lymphadenectomy [108]. Margonis and colleagues reported a morbidity of 37.4% in a review of 265 patients who
underwent surgery for ACC between 1993 and 2014, with adrenal insufficiency, pulmonary, and car- diovascular complications as the most common types [109]. Readmission following surgery for ACC has been demonstrated to be common; up to one in five patients will experience a readmission within 90 days of surgery [110]. Furthermore, patients who experience any complication have been found to have a significantly shorter median survival compared with patients without complications (25.1 months vs. 58.9 months) [109].
It has been repeatedly demonstrated that adrenalectomies performed by high-volume surgeons are associated with a lower complication rate [105,106]. A similar trend has been found between high surgeon volume and lower mortality following adrenalectomy [111]. A relationship between undergoing adrenalectomy at a high-volume center and lower postoperative complication rates has been also demonstrated inconsistently and is likely mediated by the effect of individual surgeon volume [106,112]. Few studies have evaluated the relationship between surgeon or hospital volume and postoperative outcomes specifically in ACC. Gratian and associates reviewed 2765 patients with ACC from the National Cancer Database and found that patients treated at high-volume centers underwent more radical sur- gery with higher rates of adjuvant therapy compared to patients treated at low-volume centers, yet there was no significant difference in 30-day postoperative mortality (1.9% vs. 3.7%, respectively) [113]. In a multi-institutional Italian series by Lombardi and colleagues, however, the aggressive surgery performed for ACC at high-volume centers was associated with fewer recurrences, longer time to recurrence, and longer disease-specific survival compared with outcomes at low-volume centers [28]. A meta-analysis by Langenhuijsen and colleagues included five studies that evaluated the effect of surgical volume on outcomes [29]. Similarly, treatment at high-volume centers resulted in more aggressive and open surgery, lower local recurrence and distant metastases rates, and longer time to recurrence.
As discussed, a thorough pre-operative endocrine work-up should be undertaken in all patients with suspected ACC. This is not only to rule out pheochromocytoma, but also to assess the peri- operative risks associated with cortisol-secreting ACCs. Appropriate precautions must be taken to manage post-operative adrenal insufficiency [21]. More importantly, however, patients with cortisol- secreting ACCs have been shown to have an increased rate of postoperative morbidity. Several recent studies have demonstrated an increased risk of postoperative complications, particularly wound healing issues, and longer hospital stays in patients who undergo resection of functional tumors [9,25]. Notably, patients with functional ACCs suffer from a greater number of preoperative comorbidities including diabetes, hypertension, congestive heart failure, obesity, and coagulopathy [9]. The end result is various hormonal and metabolic derangements, including hypercortisolism; such comorbidities are associated with increased rates of post-operative complications for a variety of indications and likely confound this observation.
Summary
ACC is a rare malignancy that is frequently asymptomatic at presentation, yet has a high rate of metastatic disease at the time of diagnosis. Prognosis is overall poor, particularly with cortisol- producing tumors. While the treatment of ACC is guided by the stage of disease, complete surgical resection is the most important step for the management of patients with primary, recurrent, or metastatic ACC. Radical resection with negative surgical margins is the single most important prog- nostic factor for survival in patients with ACC. To achieve the highest rate of R0 resection, open adrenalectomy is the gold standard surgical approach for confirmed or highly suspected ACC. The best post-operative outcomes are achieved by high-volume surgeons practicing at high-volume centers.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
None.
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