Minimally Invasive Surgery for Primary and Metastatic Adrenal Malignancy
Colleen M. Kiernan, MD, MPH*, Jeffrey E. Lee, MD
KEYWORDS
. Adrenalectomy . Adrenocortical carcinoma . Adrenal metastasis . Laparoscopic
. Minimally invasive . Retroperitoneoscopic
KEY POINTS
· Adrenal lesions suspicious for malignancy warrant thoughtful consideration of the pa- tient’s history, physical, biochemical, and imaging evaluation when determining the preferred operative approach.
· Minimally invasive adrenalectomy is the preferred surgical approach in selected patients with isolated, moderately sized metastatic disease to the adrenal gland, a good perfor- mance status, and otherwise favorable tumor biology.
· Localized, moderately sized adrenal lesions potentially representing a primary malignancy may be considered for a minimally invasive approach by surgeons experienced in the technique.
· Minimally invasive adrenalectomy for primary adrenal malignancy should be avoided because of the likelihood that intraoperative direct manipulation of the typically friable tu- mor will lead to tumor capsular disruption, fragmentation, and/or incomplete resection, with an associated increased risk of local-regional recurrence and peritoneal carcinomatosis.
INTRODUCTION
Minimally invasive adrenal surgery (MIS) was first described by Gagner in 1992, when he reported successful MIS extirpation of the adrenal gland in 3 patients with func- tional adrenal tumors. He proposed that the resultant decreased length of hospital stay and postoperative pain observed with the utilization of MIS would make this approach particularly helpful in the surgical management of asymptomatic adrenal lesions.1
Department of Surgical Oncology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
* Corresponding author.
E-mail address: CMKiernan@mdanderson.org
https://doi.org/10.1016/j.soc.2018.11.011
Over the past 25 years, MIS adrenalectomy has become the preferred approach for most of the patients with adrenal tumors, including but not limited to benign nonfunc- tioning tumors, benign functional tumors, selected metastases to the adrenal gland, and select indeterminate adrenal nodules (largely benign adrenal cortical adenomas). The benefits of MIS include decreased blood loss, transfusion requirement, procedure times, hospital stay, and complications when compared with open adrenalectomy.2-7
However, MIS adrenalectomy for primary adrenal malignancy (ie, adrenocortical carcinoma [ACC]) remains controversial due to the uncertainty regarding oncologic outcomes relative to open adrenalectomy.8-11
In this article, the authors discuss the evaluation of adrenal nodules concerning for malignancy and review the indications for MIS adrenalectomy in adrenal nodules sus- picious for malignancy. They also describe important patient and tumor factors to consider when making the decision to proceed with MIS adrenalectomy. The current literature on MIS adrenal metastasectomy and its association with survival by tumor type are also reviewed. The authors also discuss the available data and current recom- mendations regarding MIS adrenalectomy for ACC.
CONTENT
Evaluation of Adrenal Nodules Concerning for Malignancy
In the last 2 decades, the number of adrenalectomies performed in the United States has increased.12,13 The cause of this increase is likely multifactorial and includes increased frequency of performance and improved quality of cross-sectional abdom- inal imaging, which has resulted in increased frequency of identification of adrenal “incidentalomas” (defined as an asymptomatic adrenal nodule discovered in a patient for whom the imaging study was performed for an unrelated reason) as well as the likely identification of an increased number of functioning adrenal nodules with rela- tively milder associated symptoms (eg, “subclinical” Cushing syndrome, aldosterono- mas, pheochromocytomas). Although most of this increase in identification of adrenal nodules has been of benign adrenal tumors, the rate of adrenalectomy and more spe- cifically MIS adrenalectomy for malignancy is also increasing. 12-14
The most common indications for MIS adrenalectomy are summarized in Box 1. For the purposes of the current discussion, the authors focus on adrenal masses that are concerning for, or are known to represent, primary or metastatic cancer.
Box 1 Potential indications for adrenalectomy
Nonfunctioning adrenal nodules
Functional adrenal tumors
Pheochromocytoma
Cushing syndrome
Cushing disease
Aldosteronomas
Virilizing tumors
Myelolipoma
Adrenocortical carcinoma
Metastasis to the adrenal gland
As described in American Association of Clinical Endocrinologists and American As- sociation of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas, in the evaluation of any adrenal lesion there are 3 essential questions to address: (1) Is the tumor functional (has it resulted in circulating hormone excess)? (2) Does the tumor have radiographic features concerning for malignancy? (3) Does the patient have a history of malignancy, and is it therefore possible that the adrenal tumor represents metastatic cancer?15
The following sections review the recommended clinical, biochemical, and imaging evaluation of adrenal tumors suspicious for malignancy.
Clinical evaluation
A detailed history and physical focusing on signs and symptoms associated with func- tional adrenal tumors including signs and symptoms of hypercortisolism (weight gain, central obesity, easy bruisability, peripheral muscle wasting, hypertension, diabetes, virilization), hyperaldosteronism (hypertension, fluid retention, history of hypokalemia, muscle cramping, weakness), and pheochromocytoma (hypertension, headache, weight loss, anxiety, sweating, palpitation, or history of arrhythmia). The history should also include relevant personal risk factors (sun exposure, smoking) and family history of malignancy (including history that suggests multiple endocrine neoplasia (MEN) and/or von Hippel-Lindau syndrome) as well as a history of surveillance colonoscopy and mammogram and/or dermatologic examination for pigmented lesions. Inquiry into systemic symptoms such as weight loss, fatigue, anorexia, or back pain should also be performed, because these suggest either an advanced cancer process or, in the case of bilateral adrenal involvement by metastasis, adrenal insufficiency.
Biochemical evaluation
Recommended initial screening tests and their positive results are summarized in Table 1.
The goal of screening biochemical evaluation is to assess for the likely presence of hypercortisolism, hyperaldosteronism, or catecholamine excess. This evaluation is essential even when a malignant primary or metastatic lesion is suspected, because identification of a functional mass will affect management, and functioning adrenal cortical and medullary tumors are predicted to occur incidentally in patients with a his- tory of cancer at least as commonly as in those without such a history. Screening for hormone over-production can optionally be skipped in patients who are referred with a
| Table 1 Initial biochemical evaluation of an adrenal mass | ||
|---|---|---|
| Screening Test | Positive Result-Warrants Further Evaluation | |
| Hypercortisolism | Overnight 1 mg dexamethasone suppression test | Serum cortisol >5 ug/dL with suppressed ACTH |
| Hyperaldosteronism | Plasma aldosterone, plasma renin | Ratio of plasma aldosterone concentration to plasma renin activity >20 |
| Pheochromocytoma | Plasma free metanephrine and normetanephrine levels and/or 24 h urine metanephrines | Plasma metanephrines >3-4x normal or 24 h total urine metanephrine > 1800ug |
Abbreviation: ACTH, adrenocorticotropic hormone.
Data from Zeiger MA, Thompson GB, Duh QY, et al. American Association of Clinical Endocrinol- ogists and American Association of Endocrine Surgeons Medical guidelines for the management of adrenal incidentalomas: executive summary of recommendations. Endocr Pract 2009;15(5):450-3.
biopsy-proven metastasis to the adrenal gland; however, patients with bilateral adre- nal tumors suspected of representing bilateral adrenal metastases from a known or unknown primary site should undergo cortisol and adrenocorticotropic hormone (ACTH) determination to screen for the presence of occult adrenal insufficiency.
Approximately two-thirds of ACCs produce and release excess hormones, and known hormone hypersecretion can affect perioperative management, prognosis, and treatment of recurrent and metastatic disease and therefore should be evaluated preoperatively.16,17
In addition, the reported rate of adrenal metastases in patients with a prior history of cancer who present with an adrenal mass is 27% to 73%.18,19 Thus not all adrenal masses in patients with a prior history of malignancy will be metastatic disease; they can represent functional or nonfunctional benign adenomas or pheochromocy- tomas. Therefore, before performing a biopsy of an adrenal lesion concerning for metastasis, biochemical evaluation for pheochromocytoma is recommended to obviate the risk of hypertensive crisis.20,21
Radiographic features concerning for malignancy
The 2 most commonly used imaging modalities in the initial evaluation of patients with adrenal tumors are computerized tomography (CT) scan and MRI. In general, malig- nant adrenal lesions are heterogeneous in appearance with an irregular shape and indistinct margins. ACCs tend to be large (>6 cm) and exhibit rapid growth; in contrast, metastatic lesions can present at a range of different sizes and exhibit variable growth patterns.22 Box 2 summarizes radiographic features concerning for malignancy.
The imaging evaluation of an adrenal mass typically includes precontrast images, contrast images in both arterial and portal venous phases, as well as delayed imaging 10 to 15 minutes after contrast administration. However, if initial noncontrast imaging demonstrates an adrenal mass with Hounsfield unit (HU) density less than 10, further contrast and delayed imaging is not considered necessary due to the high specificity (98%) of that finding in predicting a lipid-rich benign cortical adenoma.23,24 In practice, pre- and postcontrast images are usually obtained sequentially as a routine within part of the same, standardized imaging protocol.
Approximately 30% of adrenal masses have an indeterminate precontrast HU (ie, be- tween 10 and 30), thus justifying contrast-enhanced CT with delayed washout.25 Pri- mary and metastatic malignant adrenal tumors tend to have increased and persistent
Box 2
Imaging features concerning for malignancy
Imaging Features Concerning for Potential Adrenal Malignancy
Size >4 cm
Growth in size >1 cm on serial imaging (within 1 year)
Irregular shape
Heterogeneous
Poorly defined margins
Necrosis
Hounsfield unit >10 on noncontrasted imaging
<60% washout on CT imaging
Hyperintense on MRI T2-weighted imaging
contrast accumulation due to neovascularization of the tumor and therefore demon- strate less washout of contrast on delayed imaging (Fig. 1). Thus, calculating the abso- lute or relative washout of indeterminate lesions can be helpful in further characterizing the lesion. Contrast washout can be calculated in 2 ways: absolute percentage washout (APW), calculated by dividing the values of enhanced HU minus the delayed HU by the value of the enhanced HU minus the noncontract HU multiplied by 100; or relative per- centage washout (RPW), calculated based on an initial CT scan with contrast and delayed scans only by diving the value of the enhanced HU minus the delayed HU by the enhanced HU multiplied by 100. An APW greater than 60% or an RPW greater than 40% is consistent with a benign adenoma (APW sensitivity 56%-100% and spec- ificity 98%-100%; RPW sensitivity 82% and specificity 92%).26-28
In summary, CT findings of precontrast density greater than 10 HU and less than 60% absolute washout are features concerning for malignancy. However, these find- ings can also be seen in pheochromocytomas, and it is emphasized also that so-called “atypical” lipid-poor but benign adrenocortical adenomas can exhibit similar imaging characteristics (eg, precontrast HU between 10 and 30), and thus imaging alone may not be diagnostic.
Because of its outstanding spatial resolution, CT is also helpful in providing the sur- geon with information regarding local invasion, the presence of bilateral or multifocal primary tumors (eg, in patients with an inherited pheochromocytoma syndrome) and the presence of extraadrenal metastatic disease (in patients with primary adrenal ma- lignancy or an extraadrenal malignancy metastatic to the adrenal gland).
MRI can also be helpful, particularly when iodinated contrast is contraindicated or avoidance of radiation exposure is desired. MRI can be particularly useful in identifying pheochromocytomas and in distinguishing among benign adenomas, malignant tu- mors, and pheochromocytomas. Adenomas typically exhibit low signal intensity on
A
B
C
Panel 1 Adrenal Adenoma
Panel 2 Adrenocortical Carcinoma
both T1- and T2-weighted images; malignant lesions demonstrate enhancement on T2-weighted images; and pheochromocytomas are characteristically intensely enhancing on T2 imaging.28 However, as with CT, there is overlap between the imag- ing characteristics of pheochromocytomas and benign primary and metastatic adre- nal malignancies; therefore, adrenal MRI results must be interpreted with the patient’s clinical history and biochemical evaluation in mind.
Role of biopsy for adrenal nodules concerning for malignancy Adrenal biopsy is generally recommended only in situations in which the results will influence manage- ment-for example, to confirm the presence of isolated metastasis to the adrenal gland in a patient with a history of malignancy at risk for adrenal metastasis in whom confirmation of the presence of metastatic cancer would result in a recommen- dation for systemic therapy. Adrenal biopsy should be avoided in lesions concerning for ACC, unless required to initiate systemic therapy (eg, a patient with borderline resectable or metastatic ACC).29-32
Before performing adrenal biopsy for suspected metastasis, biochemical evaluation for pheochromocytoma is recommended (eg, plasma fractionated metanephrines). The evaluation and management of patients with adrenal metastasis is discussed in subsequent sections.
Minimally Invasive Adrenalectomy for Indeterminate Adrenal Nodules Concerning for Malignancy
In this section, the authors review operative management of an indeterminate adrenal nodule concerning for malignancy.
An adrenal nodule can be considered indeterminate when it is intermediate in size (>4 cm but <6 cm) or has demonstrated greater than or equal to 1 cm growth in 1 year or less, has imaging characteristics that are not consistent with a benign ade- noma, and/or has clinical or biochemical features suggesting primary malignancy (eg, virilization) (see Box 2).
The size cut-off recommendations for surgery of an incidental adrenal nodule are based on reported malignancy rates, with lesions less than or equal to 4 cm with ma- lignancy rates of approximately 2% or less, 4.1 to 6 cm with malignancy rates of approximately 6%, and greater than 6 cm with malignancy rates of approximately 25%.15,18 The rate of malignancy of lesions with combinations of indeterminate but suspicious characteristics is not well described, and therefore judgment is required when deciding on surgery and optimal surgical approach for patients with, for example, relatively small adrenal nodules with indeterminate imaging characteristics or those that demonstrate some degree of growth on serial imaging.
Several different surgical approaches have been proposed for resection of indeter- minate adrenal nodules. There are clear advantages to MIS adrenal surgery when compared with open adrenalectomy in regard to acute perioperative outcomes. Mul- tiple prospective and retrospective studies have demonstrated lower blood loss, oper- ative times, hospital length of stay, and morbidity with MIS when compared with open adrenalectomy. In addition, patients report decreased pain and improved cosmesis with MIS adrenalectomy.2-7
The decision to approach these lesions using an MIS approach should be patient and surgeon specific. Surgeons should choose the approach they are most familiar with, have had sufficient training in, and have the best patient outcomes with. 33 Recent studies have shown that the median average annual volume for surgeons performing adrenalectomy is 1 case.34,35 These same studies demonstrate improved outcomes when adrenalectomies are performed by high-volume surgeons (defined as 4-6
adrenalectomies annually). For surgeons experienced in both anterior transabdominal LA as well as posterior retroperitoneoscopic (PRA) approaches, and assuming the pa- tient is eligible for either approach based on tumor type and anatomic considerations, recent randomized trial data suggest that both approaches are equally safe, with similar operative times, blood loss, postoperative levels of patient discomfort, and re- covery times.36,37 Therefore, the details of considerations provided in Table 2 help guide the operative approach in such situations.
Patient factors may dictate the operative approach. Patients who have had previous transabdominal operations may benefit from PRA to avoid potential adhesive dis- ease. 38-40 In addition, tumor size may affect the MIS approach chosen, because larger tumors (>6 cm or so) may be more challenging to extirpate via a retroperitoneal approach due to smaller working volume compared with the anterior transabdominal approach.39-41 However, it is also emphasized that properly performed PRA of small- to medium-sized tumors generally allows for minimal need to directly manipulate or grasp the adrenal gland or the tumor, thus minimizing the risk of capsular disruption, and patient recovery is at least as rapid as reported for the anterior laparoscopic approach. Patient body habitus is also an important factor to consider, because morbidly obese patients with abundant intraabdominal and retroperitoneal fat will demonstrate compression of the retroperitoneal space from their intraabdominal or- gans secondary when in the prone position. Furthermore, such patients may have such a large distance between their skin and the retroperitoneal space at the site of PRA port placement (beneath the tip of the 12th rib) that standard- or obesity- length ports are simply not long enough to permit effective access.40,41 In such pa- tients, the increased working space provided by the laparoscopic transabdominal (LA) approach, the lateral positioning that allows for gravity to help move the intraab- dominal contents away from the adrenal gland, and the common finding that subcu- taneous fat distance is actually lower in the upper anterior abdomen than posteriorly just above the hips can all favor LA.
Each approach as well as its associated advantages and disadvantages are described in Table 2. No matter the approach, it is essential to respect oncologic prin- ciples in any lesion suspicious for malignancy. Thus, the tumor must be removed completely and intact. Thus, the MIS approach is considered preferable for lesions with atypical imaging features potentially representing primary malignancy but is more likely to be representative of an atypical benign lesion, for example, intermediate size, lack of intratumor fat, and growth on serial imaging. It is emphasized that in pa- tients with clear evidence of primary ACC (adrenal tumor not suspected of representing a metastasis with necrosis, irregular borders, local invasion, or regional nodal involve- ment), it is far better to start open than to start MIS, encounter some combination of capsular disruption, fragmentation, or uncontrolled hemorrhage, and convert to open.33
Management of Adrenal Metastases
Isolated metastases to the adrenal gland most commonly originate from the lung; however, other common sites of primary malignancy include melanoma, kidney, co- lon, breast, and lymphoma. 42-47 Although prospective data are generally lacking, mul- tiple retrospective investigations have demonstrated that adrenalectomy in highly selected patients with isolated or oligometastatic disease from primary sites including the lung, melanoma, and kidney can result in prolonged survival duration and improved survival compared with similar patients who do not undergo adrenalectomy.42,44,45,47-50
Metastasis to the adrenal gland should be considered in patients with an adrenal mass and a history of malignancy that has a tendency to spread to the adrenal.
| Operative Approach | Advantages | Disadvantages | Patient Factors to Consider |
|---|---|---|---|
| Laparoscopic Transabdominal Adrenalectomy (LA) | . Large working space . Familiar orientation of anatomy | · Requires mobilization of intraabdominal organs . Must reposition for bilateral adrenalectomy | · Useful in morbidly obese patients · May be difficult in patients with prior abdominal surgery |
| Posterior Retroperitoneoscopic Adrenalectomy (PRA) | . Direct access to gland . Avoids intraabdominal cavity · Single position for bilateral adrenalectomy | . Lack of access to abdomen for exploration or control of hemorrhage . Difficulty in removing large tumors . Can be difficult in obese patients . Decreased working space | . Distance from skin to gland in obese patients . Ability to tolerate prone positioning |
| Lateral Retroperitoneoscopic Adrenalectomy | · Familiar approach to the gland for surgeons who routinely perform laparoscopic nephrectomy . Avoids the intraabdominal cavity | · Difficulty in removing large tumors . Requires more ports than LA or PRA | |
| Robotic Adrenalectomy (LA or PRA) | . Useful in patients with high BMI . Can be used for larger tumors (>5.5 cm) · 3-dimensional depth perception, additional dexterity | · Cost . Learning curve · Complexity | . Similar to patient factors to consider for LA or PRA |
Abbreviation: BMI, body mass index.
Evaluation in such patients should include imaging with abdominal CT or MRI, which should be compared with prior abdominal imaging. In addition, biochemical evaluation for a functional adrenal tumor should be pursued (see prior sections on biochemical evaluation and imaging).
If metastatic disease is suspected based on history, imaging, and biochemical eval- uation, the patient should undergo evaluation for extraadrenal disease. The evaluation required will vary by primary tumor type but may include, for example, whole body PET/CT, dedicated chest CT, and/or MRI of the brain. The decision to proceed with adrenalectomy for metastatic cancer warrants thoughtful consideration of the natural history of the underlying disease, tumor biology, presence of extraadrenal disease (if any), patient performance status, and availability of alternative therapeutic options (eg, systemic or radiation therapy). 45
Adrenal biopsy has been demonstrated to have high sensitivity, specificity, and negative predictive value for distinguishing benign from metastatic adrenal tumors (92%, 94%, and 100%, respectively).51,52 Biopsy can be particularly helpful in patients with a new, isolated adrenal mass suspicious for metastasis in a patient with a prior relevant cancer when the biopsy would (1) establish the new onset of distant metasta- tic disease, (2) allow for initiation of systemic therapy, and/or (3) confirm eligibility of the patient for entry into a clinical trial. However, not every adrenal mass suspicious for adrenal metastasis requires biopsy. Newly identified or rapidly enlarging adrenal tumors not present on prior imaging in a patient with a history of a known malignancy with propensity to metastasize to the adrenal glands (eg, lung, melanoma, renal cell carcinoma) are highly likely to represent adrenal metastasis. In such patients, and in the absence of an attractive alternative systemic treatment option or following induc- tion systemic therapy, a decision may be made to proceed directly to surgical resec- tion without preoperative biopsy.
Oncologic benefits of adrenalectomy in metastatic disease
Several retrospective investigations have examined the outcomes of adrenalectomy for metastatic disease. One study used the Surveillance, Epidemiology, and End Re- sults (SEER) database from 1992 to 2010 to match 166 patients who underwent adre- nalectomy for adrenal metastases from kidney, lung, sarcoma, colon, pancreas, and other primary sites to similar patients who did not undergo adrenalectomy. This study found that patients with soft-tissue, kidney, lung, and pancreatic tumors had a better overall survival at 3 years with adrenalectomy: sarcoma (86% vs 30%), kidney (72% vs 27%), lung (52% vs 25%), and pancreas (45% vs 12%). In this cohort, they identified shorter interval from primary diagnosis to adrenalectomy, other distant sites of dis- ease, surgery for palliation and persistent disease as risk factors for death.50
In a multicenter European study of 317 patients who underwent adrenalectomy for solid tumor metastases, the investigators found that patients with renal cell carci- noma, metachronous lesions, and isolated adrenal metastases had more favorable outcomes than patients with non-small cell lung cancer (NSCLC), colorectal cancer, or synchronous metastases. Patients with renal cell cancer who underwent adrenalec- tomy had a median survival of 84 months, NSCLC 26 months and colorectal cancer 29 months. Patients with metachronous adrenal metastases had a median survival of 30 months compared with 23 months for those with synchronous metastases. In this study, 46% of adrenalectomies were performed using an MIS approach, demon- strating the widespread application of this approach to patients with adrenal metas- tasis. Interestingly, their multivariate cox proportional hazards model, MIS adrenalectomy, was associated with a survival advantage with a hazard ratio of 0.65, 95% confidence interval 0.47 to 0.89, P = -. 009.44
In a study of 154 patients with melanoma metastatic to the adrenal gland treated at the authors’ institution (notably before the availability of the current generation of tar- geted and immune-based therapies), outcomes of patients who underwent adrenalec- tomy were compared with outcomes of those who did not undergo adrenalectomy. Twenty-two patients underwent surgery. Twenty patients were rendered disease free by adrenalectomy alone (n = 14) or adrenalectomy with concomitant extraadrenal metastasectomy (n = 6). Patients who underwent adrenalectomy had an improved overall survival compared with those managed nonoperatively (20.7 months vs 6.8 months, P <. 001). This study suggests that metastatic melanoma isolated to the adrenal, normal lactate dehydrogenase, symptoms related to adrenal metastasis, a disease-free interval of 1 year or more, and limited extraadrenal disease that can also be resected may be reasonable selection criteria when considering to proceed with adrenalectomy, although this treatment paradigm should be updated in the era of modern melanoma systemic therapy.49
Operative approach to adrenal metastatic disease
Minimally invasive adrenalectomy has become the preferred operative approach for management of adrenal metastasis. It has been demonstrated to be both safe and oncologically appropriate in selected patients.45,46,53-57 A retrospective review of 94 adrenalectomies for isolated adrenal metastases (63 open and 31 MIS) found no dif- ference in local recurrence, margin status, disease free interval, or overall survival based on the surgical approach chosen. Moreover, MIS adrenalectomy was associ- ated with decreased blood loss (106 vs 749 cc, P <. 001), operative time (175 vs 208 mins, P = . 04), length of stay (2.8 vs 8 days, P <. 001), and complication rate (4% vs 34%, P <. 01).46
However, other studies have suggested that for large tumors (>5-6 cm) MIS adre- nalectomy is associated with increased risk of a margin-positive resection and an increased complication rate.47 Therefore, when determining the operative approach to adrenal metastases, tumor size and radiographic evidence for local invasion should be considered. Finally, MIS adrenalectomy, particularly via a PRA approach, may limit the ability to evaluate and treat other intraabdominal sites of metastasis (eg, mela- noma metastatic to the small intestine) and may therefore be relatively contraindicated in patients with known or suspected extraadrenal but intraabdominal sites of oligome- tastasis for which concomitant surgery would be desired.
Adrenocortical Carcinoma
ACC is a rare primary adrenal malignancy with an annual incidence of 1 to 2 per million.58,59 It is an aggressive tumor that carries a poor prognosis. Most patients pre- sent with locally advanced or metastatic disease not amenable to surgical resection.
ACC is commonly diagnosed during evaluation of symptoms related to hormone excess because approximately two-thirds of ACCs produce and release excess hor- mones. 16,17 Up to one-third of patients will present with nonspecific symptoms due to tumor growth such as abdominal or flank pain, abdominal fullness, or early satiety or be found incidentally on imaging for unrelated medical issues. 60
Biochemical evaluation should include screening for cortisol overproduction, pheo- chromocytoma, and aldosteronoma if hypertensive and/or hypokalemic. Sex hor- mones should be evaluated in anyone with virilizing features or imaging characteristics suspicious for ACC.
Imaging of an adrenal mass suspicious for ACC should include an adrenal protocol CT or MRI. On CT, ACC is typically identified as a large heterogeneous mass with indis- tinct borders. Invasion of adjacent structures is common, including liver, kidney, and
vena cava on the right side and pancreas, spleen, renal vein, and kidney on the left side. Vena cava tumor thrombus is common, often originating at the level of the right adrenal vein and extending into the retrohepatic cava or extending from the left renal vein into the infrahepatic vena cava. Regional lymphadenopathy may also be seen. If ACC is sus- pected based on imaging, a CT of the chest should be performed to evaluate for pulmo- nary metastasis; pulmonary emboli are also common in patients with ACC.
Operative approach to adrenocortical carcinoma
Complete surgical resection with negative margins is the only curative option for ACC.9,58,61-63 Thus the operative approach chosen must have the highest likelihood of achieving this goal. Controversy continues to exist on the role of an MIS approach in surgical management of primary ACC.
Proponents of the MIS approach to ACC cite retrospective series that conclude that an MIS approach is safe and can achieve similar oncologic outcomes for highly selected patients with relatively “small” tumors (<10 cm) without evidence of local in- vasion, provided oncologic principals are respected.64-68 In contrast, proponents of open adrenalectomy cite retrospective studies of referral populations of patients with ACC that have identified increased rates of peritoneal carcinomatosis, capsular disruption, positive margins, and recurrence, as well as poorer stage-specific survival, in patients undergoing MIS compared with open resection of primary ACC.9-11 There are no randomized controlled studies comparing MIS to open adrenalectomy for ACC and almost certainly never will be due to the rare nature of the disease and other considerations.
The American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons, the Society of American Gastrointestinal and Endoscopic Sur- geons, as well as the European Network for the Study of Adrenal Tumors guidelines all agree that open adrenalectomy should be performed if ACC is suspected. 15,33,69
ACC is often a soft tumor with consistency similar to friable adrenal cortex; capsular disruption and fragmentation are easy to induce, particularly during direct tumor manipulation that commonly occurs in attempted MIS of these characteristically large tumors. Furthermore, ACC tends to invade through the tumor capsule with micro- scopic disease present at the gland surface; thus minimizing direct contact with the tumor surface is essential to avoid violating the tumor capsule or causing disruption of disease at the surface of the gland.58 Thus, the authors endorse with the aforemen- tioned consensus guidelines favoring open adrenalectomy for ACC, because the open approach they believe maximizes the likelihood of complete en bloc resection of an intact tumor and facilitates an appropriate regional operation, including any indicated lymphadenectomy.
The role of lymph node dissection in treatment of ACC remains unclear; there is no consensus regarding the extent of lymph node dissection that should be routinely per- formed, if any. Reported rates of lymph node removal in studies using large national databases are low (17%-30%).16,70,71 Standardization of regional lymphadenectomy has been proposed to include first-order drainage nodes including the renal hilum lymph nodes, celiac lymph nodes, and the paraaortic and paracaval lymph nodes above the renal pedicle and ipsilateral to the adrenal gland.72 However, this definition has not been widely adopted. A study of the German ACC Registry reports that in 283 patients with ACC formal lymph node dissection based on adrenal lymphatic drainage patterns results in a reduced risk of tumor recurrence (hazard ratio [HR] = 0.65, P = . 42) and disease-related death (HR = 0.54, P = . 049).71 The rate of lymph node dissection is lower in adrenalectomies performed using an MIS approach for ACC than in those performed open.73 Important missing data in these retrospective series
is the proportion of patients who underwent lymph node removal of involved regional nodes for preoperatively or intraoperatively defined indications rather than routinely (that is, because of the presence of suspicious nodes identified either on preoperative imaging or intraoperatively, or because the involved nodes were within the field of adjacent organ resection, eg, pancreas, spleen, or kidney). The authors’ current prac- tice is to resect lymph nodes based on these latter criteria rather than performing routine lymphadenectomy.
Patients with primary ACC can present with formally resectable tumors, but with characteristics arguing against immediate surgery, including an unacceptably high risk for incomplete resection or early recurrence or an unacceptably high risk of peri- operative morbidity or mortality. Such characteristics included a large and extensive primary tumor and need for multiorgan resection (liver, pancreas, kidney), significant vena cava tumor thrombus, documented or suspected oligometastatic disease, and potentially correctable comorbidities (severe Cushing syndrome, pulmonary emboli). Such patients may be considered to have borderline resectable ACC and be candi- dates for preoperative (neoadjuvant) systemic therapy. Early experience suggests such an approach, combined with appropriately aggressive surgical resection, can result in good outcomes compared with patients treated with upfront open surgery.29
Finally, the importance of surgeon experience in resection of ACC cannot be under- emphasized due to the often-complex nature of these tumors. Lack of experience with adrenal tumors can lead to tumor rupture and/or positive margins regardless of approach. Several studies have demonstrated higher rates of complete resection and improved outcomes when ACCs are managed at centers with expertise. 62,68,74-76 In this context it is important to emphasize that in the United States 45% of adrenal- ectomies for ACC are performed in community hospitals, 30% in academic centers, and only 15% in National Cancer Institute-designated Cancer Centers.7º Referral to high-volume centers, experienced in treating patients with ACC, should be considered before proceeding with resection, regardless of operative approach.
CLINICAL EXAMPLES AND MANAGEMENT
Patient 1: a 43-year-old woman presented with chronic back and abdominal pain. She had a CT scan performed 5 years ago that demonstrated a 2.7 cm L adrenal nodule. She had no signs or symptoms of hormone hypersecretion. She had no previous his- tory of malignancy. A CT scan performed during current evaluation demonstrated a 4.4 cm left adrenal nodule (Fig. 2). Biochemical evaluation included baseline AM cortisol of 9.6 ug/dL and ACTH of 6 pg/mL. A 1 mg overnight dexamethasone test failed to suppress her AM cortisol level. Her plasma metanephrines were normal. She was diagnosed with subclinical Cushing syndrome. Although increasing in size, the mass had the appearance of a benign adrenal adenoma on imaging. She was therefore recommended to undergo MIS via PRA. Pathology revealed a benign adre- nal adenoma.
Patient 2: a 67-year-old man presented with metastatic melanoma from an unknown primary site to the subcutaneous tissue, lung, bone, gastrointestinal tract, and left ad- renal gland. He received immune checkpoint inhibitor and subsequently demon- strated complete response at all sites except for the left adrenal gland. His body mass index is 39, and on review of imaging he was thought to be of borderline habitus for PRA due to increased distance between the skin and retroperitoneal space (see Fig. 2). He therefore underwent MIS via an anterior LA. Pathology was consistent with treated melanoma, with no viable tumor cells present.
A
B
35 mm
68 mm
C
Patient 3: a 51-year-old woman presented with hypertension and hirsutism. A CT scan was performed for abdominal pain suspected of representing diverticulitis. A 9 cm right adrenal mass was identified. The mass was heterogeneous and irregular (see Fig. 2). Biochemical evaluation revealed elevated cortisol that failed to suppress on overnight dexamethasone administration and an elevated testosterone level. Based on clinical and imaging findings, a presumptive diagnosis of ACC was made. She underwent open adrenalectomy. Pathology revealed ACC with free margins (R0 resection).
SUMMARY
Primary and metastatic cancers involving the adrenal gland are uncommonly encoun- tered in most surgical practices. Patients known or suspected of having such tumors warrant thoughtful consideration of relevant details of their history, physical, biochem- ical, and imaging evaluation in determining the need for operative intervention and the optimal surgical approach. Selected patients with adrenal lesions potentially repre- senting primary malignancy (<6 cm in size with indeterminate imaging findings) can
safely undergo a minimally invasive operation in experienced hands, provided stan- dard oncologic principles are adhered to. It seems reasonable to offer selected pa- tients with isolated metastatic disease to the adrenal gland surgical resection, and MIS via PRA or LA is the preferred approach when anatomically feasible (ie, moder- ately sized tumor without local-regional invasion). Finally, primary ACC should be removed using an open surgical approach, with a focus on complete en bloc resec- tion. MIS adrenalectomy for ACC should generally continue to be avoided due to the risk of poorer associated outcomes, including tumor capsular disruption with associated incomplete resection, positive resection margins, and risk of early local- regional recurrence and peritoneal carcinomatosis.
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