Adrenocortical Cancer Treatment
Samuel E. Long, MD*, Barbra S. Miller, MD
KEYWORDS
. Adrenal cancer . Adrenocortical carcinoma . Adrenalectomy . Mitotane . Cancer
. Cortisol . Surgery
KEY POINTS
· Adrenocortical carcinoma is a rare cancer with poor prognosis.
· Evaluation of adrenal masses requires both assessment of imaging characteristics and investigation for evidence of adrenal hormone excess.
· Fine-needle aspiration of adrenal tumors is rarely indicated during evaluation of adrenal masses.
· Surgery is the primary treatment modality for management of early stage adrenocortical carcinoma.
· Mitotane and cisplatin-based chemotherapy are considered first-line treatment for meta- static adrenocortical carcinoma.
INTRODUCTION
Considered a rare malignancy with an incidence of 1 to 2 per million in the population, adrenocortical carcinoma (ACC) has historically been associated with poor outcomes; however, knowledge about ACC has increased significantly over the past 2 decades leading to advances in care.1-3 Surgery remains the primary modality to achieve cure in patients with early stage disease. In those with advanced disease, mitotane, chemotherapy, and other surgical and nonsurgical interventional therapies are now used in various combinations. This has allowed for improved survival in a greater num- ber of patients compared with historical controls. The following material focuses on the evaluation and management of patients with ACC.
PREOPERATIVE EVALUATION
The initial evaluation of any patient with suspected ACC begins with a thorough his- tory and physical examination, assessing for any clinical evidence of adrenal
* Corresponding author.
E-mail address: selong@med.umich.edu
hormone excess.2-4 New onset hypertension, edema, weight gain, changes in sec- ondary sexual characteristics, and features consistent with Cushing’s syndrome may be associated with ACC. Patients should be questioned about a history of other previous malignancy or new symptoms that suggest an undiagnosed malignancy of nonadrenal origin as a suspicious adrenal mass may represent metastatic disease. Melanoma, breast cancer, renal cell cancer, and lymphoma are most commonly associated with involvement of the adrenal glands, but other malignancies have been described.3,4
More than half of patients with ACC will have biochemical evidence of adrenal hor- mone excess, most commonly cortisol and androgens (Fig. 1).5 Excess aldosterone production alone is rarely seen in patients with ACC.5,6 Benign aldosteronomas are generally small, ranging from 1 to 2 cm on average. Therefore, a larger aldosterone- producing tumor not meeting imaging criteria for being benign could be malignant. Malignant aldosterone-producing tumors are significantly smaller on average than other ACCs.6,7 A comprehensive biochemical evaluation is carried out in systematic fashion (Table 1), investigating for end-products of steroid synthesis as well as inter- mediaries, both of which may be used as tumor markers going forward to assess for evidence of tumor recurrence or disease progression.2,3,8 It is imperative to rule out pheochromocytoma by biochemical analysis before considering any operative intervention.2,9,10
IMAGING
Computed tomography (CT) is the most common modality used to evaluate adrenal masses; however, unless done using an adrenal protocol, it is unlikely the mass will be fully evaluated.2,11 MRI12 and/or PET-CT13,14 also have a role in the evaluation of adrenal abnormalities, especially in heterogeneous tumors where percent washout on CT should not be calculated or when imaging may be discordant from clinical sus- picion. ACC is typically 18F-fluorodeoxyglucose (FDG) avid, although tumor necrosis is
Hormones Produced
45%
43%
40%
35%
30%
25%
22%
20%
17%
15%
10%
8%
5%
5%
3%
1%
0%
No hormone
Androgen + Cortisol
Cortisol only
Androgen only
Mineralocorticoid
Estrogen only
Multiple hormones
| Table 1 | |
| Biochemical evaluation of adrenocortical carcinoma | |
| Initial Biochemical Evaluation of ACC | |
| Mineralocorticoids | Metabolic panel, aldosterone, renin |
| Glucocorticoids | ACTH, 24-h urine study for cortisol OR 1 mg DST |
| Androgens | DHEA-S, testosterone (women only), 17-beta-estradiol (men and postmenopausal women), 17-OH progesterone, 11-deoxycortisol, androstenedione |
| Catecholamines | Plasma and/or 24-h urine metanephrine and normetanephrines |
Abbreviation: DST, dexamethasone suppression test.
common and may result in non-18F-FDG avid areas of tumor.13,14 Table 2 lists the characteristics and criteria that may assist in differentiating benign from indeterminate adrenal masses.15 Imaging should also be used to guide the surgical approach, identify the potential need for en-bloc resection of any adjacent structures, and iden- tify any concerning lymph nodes or other potential sites of metastatic disease. In pa- tients with suspected ACC, imaging should include the chest to evaluate for metastatic disease.2,3,8,15
In the past, the decision to intervene on an adrenal mass was often based on size. Tumor size greater than 4 to 6 cm was historically used as a cut-off to proceed with surgery given the increased rate of malignancy with larger tumors.16 This has since been superseded by imaging characteristics (ie, washout patterns, lipid content, het- erogeneity, etc.) which have more prognostic value than size alone.2,3,8,15 A purely nonfunctional tumor with benign imaging characteristics does not necessarily need to be resected. If an incidental adrenal mass is noted but appears benign, short- term interval follow-up with repeat imaging at 6-12 months is now recommended.17 If a benign-appearing tumor continues to reveal evidence of growth or causes compressive symptoms of adjacent structures, then it should be resected.
BIOPSY
Fine-needle aspiration has a limited role in the evaluation of adrenal masses. 18-20 Seeding of the needle tract has been reported when ACCs have been biopsied. The few instances in which biopsy may be indicated include the following: (1) when metastatic disease from another primary tumor is suspected; (2) if a patient has unresectable disease and tissue confirmation is required before beginning
| Size | CT | MRI | PET CT | |
|---|---|---|---|---|
| Benign | <4 cm if other benign internal characteristics | <10 Hounsfield units, > 50% washout | >50% chemical shift | Tumor SUV <3.4 Tumor: Liver SUV ratio <1.4514 |
| Indeterminate | >4-6 cm if other indeterminate characteristicsª | >10 Hounsfield units, <50% washout | <50% chemical shift | Tumor SUV >3.4 Tumor: Liver SUV ratio >1.4514 |
a Indeterminate characteristics: Heterogeneous internal attenuation, calcification, necrosis, irreg- ular borders, local invasion, intravascular tumor thrombus, adjacent lymphadenopathy.
chemotherapy; (3) the patient is a poor operative candidate with significant comor- bidities. Other less common indications for biopsy include a suspected adrenal lym- phoma or infectious causes such as tuberculosis or histoplasmosis, all of which usually present with bilateral abnormalities.18 Fine-needle aspiration should never be performed until pheochromocytoma has been ruled out as hypertensive crisis may result. 10
PREOPERATIVE CONSIDERATIONS
Patients should undergo standard evaluation for fitness for surgery. Patients with ev- idence of hormone excess, especially those producing cortisol, are at increased risk for complications and difficulty recovering from surgery.2,8,15 There are several med- ications that can be used preoperatively to control the effects of hormone excess.3,8 In patients with hypercortisolism, inhibitors of cortisol production (ketoconazole, mito- tane, metyrapone, etomidate) as well as glucocorticoid receptor antagonists (mifepris- tone) can be used.21 It is critical to remember that cortisol levels cannot be used to guide therapy when using glucocorticoid receptor antagonists and that dexametha- sone should be used instead of hydrocortisone for treatment of Addisonian crisis when patients are taking mifepristone. For mineralocorticoid excess, either spirono- lactone or eplerenone can be used to control hypertension or hypokalemia in Conn syndrome and some cases of severe cortisol excess.3,8 Additional medications for management of adrenal hormone excess are outlined in Table 3.
SURGICAL RESECTION
Minimally invasive adrenalectomy, whether performed by laparoscopic, retroperito- neoscopic, or robotically assisted approaches, has become the standard for resection of benign tumors of appropriate size.2,15 Open resection is preferred for adrenal masses known or strongly suspected to be ACC.2,22 For those with indeterminate tu- mors not meeting imaging criteria for being benign, controversy with regard to the operative approach remains.23-27 Disease recurrence in some studies has been shown to occur earlier and more often in patients treated for ACC by minimally inva- sive approaches due to a higher rate of intraoperative tumor spill and positive margins in some studies.23,25,27 Overall survival was also found to be shorter in Stage 1 and Stage 2 patients who underwent laparoscopic resection.27
| Type of Hormone Excess | Primary Medication | Alternative Medications |
|---|---|---|
| Cortisol | Ketoconazole, mitotane, metyrapone, mifepristone ª | Etomidateb |
| Aldosterone | Spironolactone | Eplerenone, amiloride |
| Testosterone | Spironolactone | Abiraterone®, Ketoconazole“ |
| Estrogen | Tamoxifen | Raloxifene, anastrozole, letrozole, exemestane |
a Selection of medication depends on degree of hormone excess.
b Patients should be monitored in an intensive care unit setting.
” Off-label use.
RIGHT OPEN ADRENALECTOMY
Open adrenalectomy28 is typically performed through a wide right subcostal incision that extends across to the left side (with or without extension to the xiphoid process). Other approaches, including a midline incision or Makuuchi incision29 can be per- formed. A thoracoabdominal incision is rarely required. Systematic exploration of the abdomen is pursued, looking for evidence of metastatic disease. Ultrasound of the liver can be performed, looking for metastases that may not be visualized on preoperative imaging. With a right ACC, the vena cava is also inspected for either obvious invasion or intracaval tumor thrombus. A self-retaining tractor such as a Thompson or Omni retractor is then placed. This allows retraction of the ribs and for full mobilization of the liver to provide access to the inferior vena cava, right adrenal gland, and kidney. It is advantageous to release the left coronary and triangular ligaments as well to allow for full rotation of the liver. If tumor is found to be invading the posterior aspect of the liver, a thin rim of liver can be resected along with the specimen as part of the anterior margin. In general, the posterior peritoneal lining should be kept on the anterior surface of the tumor as part of the anterior margin. Dissection then occurs inferiorly over the superior half of the kidney, taking the posterior peritoneal lining and any fat over the su- perior half of the kidney to provide a sufficient inferior margin. This is continued to the plane between the adrenal gland and kidney. If there is any question of local invasion into the kidney parenchyma or renal hilar vessels, partial nephrectomy or total nephrec- tomy should be performed to ensure an R0 resection. The surgeon should refrain from trying to create a plane that does not exist, as this can result in tumor rupture, dissem- ination, and early recurrence. In some cases, the kidney may be able to be spared if the renal hilar vasculature is not involved and the renal capsule can be included as part of the inferior margin. The operation continues, taking all retroperitoneal fat surrounding the tumor to the abdominal side wall as part of the lateral and posterior margins, with dissection exposing and sometimes including part of the posterior musculature if necessary. The dissection is carried superiorly to the level of the diaphragm. If tumor seems to involve the diaphragm, a portion of the diaphragm can be excised and closed primarily or with mesh. Lastly, the medial dissection is performed, starting over the anterior aspect of the vena cava, keeping any fat between the tumor and the vena cava with the tumor. The medial aspect of the dissection is an area at high risk for microscopic residual disease, given little intervening fat between tumor and vena cava. Once the adrenal vein is identified, it is ligated and divided. The tumor is then removed and marked with sutures. If adherence to or invasion of the adrenal vein or vena cava is identified, various methods can be used to obtain negative medial margins or extract tumor thrombus, including primary resection and closure if the vena cava is not narrowed greater than 50%, use of a bovine pericardial or vein patch, or resection and replacement of the vena cava with a ringed polytetrafluoroethylene graft. Rarely, venovenous or cardiopulmonary bypass is required. Clips can be placed in the surgical bed to facilitate future radiation therapy. The abdomen is then closed.
LEFT OPEN ADRENALECTOMY
An appropriate incision is again made. Once adequate exposure is obtained, the pro- cedure begins with mobilization of the left colon by taking down the white line of Toldt; this is continued superiorly and the spleen is then released from its attachments to the level of the esophageal hiatus. The stomach, spleen, pancreas, and colon are all retracted medially if not involved by tumor in order to visualize the kidney, left adrenal gland, and aorta. The remainder of the operation is carried out in a similar manner to the contralateral side, making sure to include all the surrounding and retroperitoneal fat
along with the adrenal gland. The left adrenal vein is typically identified inferomedially near the 7 or 8 o’clock position on the gland and is ligated at its insertion into the left renal vein. Careful assessment of the left adrenal vein and its junction with the left renal vein is necessary to ensure no intravenous thrombus remains. En-bloc resection of involved organs, most often the kidney, distal pancreas, and spleen, may be required.
POSTOPERATIVE CONSIDERATIONS
Patients with ACC who undergo resection are typically admitted postoperatively for anywhere from 3 to 7 days. In patients with evidence of preoperative hormone excess, serial assessment of electrolytes, volume status, and blood pressure is necessary. In those who have overt hypercortisolism, postoperative steroid supplementation is almost always required, whereas those with subclinical hypercortisolism or lack of cortisol suppression after dexamethasone suppression testing should undergo testing on postoperative day one to determine the need for steroid supplementation.30 The total daily dose of steroids should be administered in 2 or 3 divided doses, with the larger dose in the morning to replicate the usual early morning surge of cortisol. Hydro- cortisone is the preferred steroid for replacement. Prednisone is avoided, as it in- creases the length of time for recovery of the hypothalamic pituitary adrenal axis. Furthermore, any patient who has undergone an adrenalectomy for ACC is at risk of an Addisonian crisis and should be counseled about the need for steroid supplemen- tation should this occur. This risk is higher in patients who have undergone bilateral adrenalectomy or unilateral adrenalectomy requiring postoperative steroid supple- mentation and in those taking mitotane. Because mitotane blocks cortisol production and is also an adrenolytic, patients require steroid supplementation when treated with this medication.2,3
STAGING AND PROGNOSIS
Multiple staging systems exist for ACC. The 2 staging systems that are most widely used are the American Joint Committee on Cancer (AJCC) 8th Edition31 and the European Network for the Study of Adrenal Tumors (ENSAT). 32 The TNM classification for adrenal cancer was modified in the 8th Edition of the AJCC/UICC staging system to mirror the TNM classification of the ENSAT system. Additional modifications have been proposed over the past decade to further enhance the prognostic ability of these staging systems and include incorporation of age, gender, and tumor grade.33,34 As more is known about the tumor biology of ACC, the incorporation of genomic and pro- teomic factors may also lead to better prognostication.35
There are multiple factors that influence prognosis in patients with ACC, with initial stage and tumor biology being most important.2,3,5,8,27,33,35-39 Five-year survival for patients with ACC ranges from approximately 65% in patients with stage I disease to less than 10% in patients with stage IV disease.1-5 Production of cortisol, high tu- mor grade, and increasing stage consistently predicts worse outcomes across multi- ple studies. 1-5 Ki-67 index is used as an alternative to mitotic rate and independently predicts recurrence, even following R0 resection.2
GENETIC TESTING
All patients diagnosed with ACC, as well as those with a known family history of a ge- netic mutation or other tumors associated with a genetic syndrome linked to adrenal cancer, should have an in depth family history taken and be referred to a genetic coun- selor for genetic testing.2,8,40 Every adult patient with ACC should be offered genetic
testing for Li-Fraumeni and Lynch syndromes.2,8,40 Other hereditary syndromes asso- ciated with development of ACC include MEN-1, Beckwith-Wiedemann syndrome, fa- milial adenomatous polyposis, neurofibromatosis type I, and Carney syndrome.2,8,40
ADJUVANT THERAPY
Even after complete resection, many experts will agree that adjuvant therapy is advan- tageous due to the high rate of local and distant recurrence following initial resection of ACC.2 Mitotane, a derivative of the insecticide DDT, inhibits steroidogenesis and has a cytotoxic effect on cells of the adrenal cortex. It is the only medication specifically approved by the Food and Drug Administration for treatment of ACC. The usual dose is 5 to 15 g/d with target plasma concentrations of 14 to 20 mg/L.2,41 Other cyto- toxic chemotherapy regimens are not routinely used in an adjuvant manner but may be used in highly selected situations for patients at high risk for distant metastasis.2 A new clinical trial to assess the impact of adjuvant cytotoxic chemotherapy is planned.
RADIATION THERAPY
Historically, external beam radiation therapy (XRT) was not considered beneficial for treatment of ACC. Over the past 2 decades, 2 high-volume centers have reported sig- nificant impacts on locoregional control with use of XRT in both adjuvant and palliative settings, 42,43 and forthcoming data suggest improved survival. Indications for XRT include those undergoing R1 or R2 resection. Following an R0 resection, XRT is considered in those with adverse risk factors such as high-grade disease, nodal involvement, lymphovascular invasion, and those having undergone laparoscopic resection, given the higher risk for local recurrence in some studies.2,3,27,38,42,43 Stereotactic body radiotherapy is a more targeted alternative to conventional XRT that can be successfully used to treat small volume disease, particularly in the lungs and liver. This is well tolerated and treatment duration is much shorter (days vs weeks).
OTHER SURGICAL SITUATIONS-STAGE IV DISEASE AT PRESENTATION AND BORDERLINE RESECTABLE ADRENOCORTICAL CARCINOMA
An initial surgical approach is typically warranted for any patient who presents without evidence of metastatic disease and has an adrenal mass that appears amenable to an R0 resection based on preoperative imaging. Assessment of performance status and especially degree of debilitation due to any hormone excess is key to determining risk before offering surgical resection. Any evidence of metastatic disease should prompt discussion in a multidisciplinary setting with consideration for initial systemic treat- ment with chemotherapy (etoposide, doxorubicin, and cisplatin [EDP]) and mitotane rather than resection of the primary lesion.2,22,38,44 The decision of when to offer meta- stasectomy at the time of initial presentation depends on many factors. If tumor response to systemic therapy is noted or at least stable without evidence of new le- sions and all tumor can be resected or treated in some way with a combination of local therapies, resection may be pursued.38 If additional metastatic lesions appear, XRT to the primary tumor may be offered, as surgical resection of the primary tumor usually does not alter survival.3,8 Some may consider resection of the primary tumor if control of hormone excess is problematic, although control is often achievable with currently available medications, and subsequent disease progression may overcome this perceived benefit of resection relatively quickly.45
Locally invasive tumors without evidence of other metastatic disease, in which an R0 resection would be unlikely, may benefit from neoadjuvant therapy. Should
response to mitotane and/or chemotherapy be evident, surgery may then be under- taken with an improved chance of an R0 resection. In a series from MD Anderson, pa- tients with initially unresectable or borderline unresectable ACC who underwent neoadjuvant chemotherapy had a median disease free survival of 28 months as opposed to 13 months in patients who underwent surgery alone.46 This approach also allows for the disease to declare itself, as those with progression of disease (pri- mary tumor or new metastases) will likely not benefit significantly from resection.
RECURRENT DISEASE
Approximately 70% to 90% of patients with ACC will experience cancer recurrence at some point.38,47 Most commonly, initial recurrence occurs in either the tumor bed or the lungs.38 Survival has been found to vary based on site and extent of initial disease recurrence. Although metastases to the lungs occurred earlier, they were associated with longer survival compared with those with initial metastasis to the peritoneal cavity or metastases involving multiple organ systems.38
For patients found to have metastatic disease, mitotane is usually given in combina- tion with EDP as first-line therapy. Streptozocin plus mitotane is considered second- line therapy.48 Approximately 30% of patients will respond to mitotane- and/or cisplatin-based therapy. Given the poor long-term response of ACC with traditional chemotherapy, there has been increasing focus on providing more individualized care using targeted therapies based on actionable mutations identified using molec- ular testing.2,8,22,35 Trials are ongoing.
In the past, reoperation for recurrent ACC was rarely undertaken; however, more recent work has identified some patients who will benefit from reoperation.38,45,47 Mul- tiple factors must be considered before proceeding with resection, including having an understanding of specific tumor characteristics (tumor grade, Ki-67 index), extent of disease to be resected, conduct of the initial resection (oncologic technique, R type-0,1,2), recurrence free interval and tempo of disease, and response to medical therapy.38 Those with low-grade tumors often have slower disease progression compared with those with high-grade tumors, and thus survival may be prolonged with resection of recurrent disease.2,33,38 Patients with recurrent metastatic disease are usually subjected to treatment with mitotane and EDP for 2 to 3 rounds before sur- gery and reimaged to determine response.38 In those patients with response or stabil- ity, resection can be considered where all tumor can be resected or resection is necessary due to threat to a vital structure with continued growth or inability to control hormone excess. Other considerations include a patient’s functional status and ability to tolerate surgery as well as consideration of tempo of disease. Reresection with ev- idence of new metastases on the next surveillance scan is not desirable, and instead a balance between proceeding with resection for prolonging survival and quality of life must be found.38 Because of this, there has been a shift from formal surgical resection to utilization of various types of localized therapy to address metastatic disease in certain sites (lung, liver).2,38,49,50 An algorithm for management of metastatic disease developed by the University of Michigan Endocrine Oncology group is shown in Fig. 2.38
HEATED INTRAOPERATIVE PERITONEAL EXTRACORPOREAL CHEMOTHERAPY FOR PERITONEAL CARCINOMATOSIS
Although heated intraoperative peritoneal extracorporeal chemotherapy (HIPEC) has been studied more extensively in the treatment of mesothelioma, ovarian, appendi- ceal, colorectal, and gastric malignancies, there may be a role for patients with
Imaging Evidence of Recurrent Adrenal Cancer
Disease involves single organ/area
Disease involves multiple organs/areas
Able to attain NED with surgery or other local intervention
Unable to attain NED with surgery or other local intervention
Prior Recurrence? {if >2 previous operations, consider intervention vs best medical therapy on an individual basis)
Mitotane ± Chemotherapy (EDP)
RFI > 12 mo
RFI < 12 mo
Favorable characteristics Low grade tumor Ki-67<30% No cortisol excess
Open resection RO resection No intraoperative tumor spillage Limited comorbidities
Unfavorable characteristics High grade tumor Ki-67>30% Cortisol excess Laparoscopic resection R1 resection Intraoperative tumor spillage Serious comorbidities
Response or stability after at least 2 cycles of treatment ª
Progression after at least 2 cycles of treatment
Consider surgery in context of expected future recurrence and duration of survival
Able to attain NED of all sites with surgery or other local intervention
Unable to attain NED with surgery or other local intervention
Role for debulking?
Peritoneal Cavity
Lung
Liver
Tumor Bed
Other
53 metastases Surgery vs. other local tissue sparing therapy (SBRT, RFA, MWA
>3 metastases Best medical therapy
1. Remove remaining retroperitoneal fat in area 2. Consider XRT after surgery if not already done
1. Resection of all visible disease.
Site Dependent
Hormone excess unable to be controlled medically or threatened vital structure
No hormone excess or threatenedvital structure
Single lobe
53 cm Image guided intervention (RFA, MWA, SBRT, cryoablation, etc.)
>3 cm Formal surgical resection ± image guided intervention if other smaller sites
Both lobes Combination of formal vs. tissue sparing surgical resection ± image guided intervention depending on size and distribution of metastatic disease OR Best medical therapy
2. Consider HIPEC under study protocol
cryoablation, etc.)
Consider surgery in context of expectedfuture recurrence and duration of survival
1. Best medical therapy (other chemotherapy options if medically fit) 2. Best supportive care if not a candidate for chemotherapy 3. Consider clinical trial
ARTICLE IN PRESS
Adrenocortical Cancer Treatment
ACC.51-53 HIPEC was previously investigated as an adjunct for the treatment of recur- rent intraperitoneal ACC. Initial outcomes were not significantly changed, and the treatment itself was associated with significant morbidity and mortality. With improved understanding of the disease process and better patient selection, there may be a role for HIPEC in carefully selected patients.52,53 Currently, new studies are underway. Chemotherapeutic agents used for HIPEC in ACC include cisplatin, carboplatin (for those with reduced renal function), mitomycin C, and oxaliplatin. 52,53
SUMMARY
Despite being difficult to treat malignancy, advances in treatment and overall survival are being made. In large part, this is due to an increased understanding of factors identified at the time of pathologic review, including molecular profiling, which allows for selection and initiation of adjuvant treatment at an earlier time. As surgery remains the primary modality to achieve cure, it is critically important that appropriate onco- logic techniques are used to minimize local and peritoneal recurrence, reserving sys- temic therapy to control distant disease. Careful selection of patients who may benefit from localized approaches to therapy (surgical or other intervention) can also lead to improved outcomes. With continued collaborative effort-mitotane plus traditional chemotherapy, utilization of molecular profiling to identify actionable mutations and pathways for new drug development and immunotherapies-a comprehensive multi- disciplinary approach to treatment will hopefully continue to drive progress forward.
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