Surgical Management of Adrenocortical Carcinoma
Gustavo G. Fernandez Ranvier, MDa, William B. Inabnet III, MDb,*
KEYWORDS
. Adrenocortical tumor . Adrenocortical carcinoma
. Metastatic adrenocortical carcinoma . Open adrenalectomy . Mitotane treatment
. Chemotherapy for adrenocortical carcinoma
KEY POINTS
· Adrenocortical carcinoma (ACC) is one of the most aggressive malignant endocrine tumors.
· ACC has a bimodal age distribution, with the first peak occurring at the age of 5 years and the second in the fourth to sixth decade of life.
· A comprehensive biochemical evaluation is required before surgical resection.
· Complete surgical resection is the first-line treatment of ACC.
· The definite diagnosis of ACC is made by the presence of preoperative locoregional inva- sion or distant metastases on imaging studies or the presence of capsular or vascular in- vasion on postoperative pathology specimens.
INTRODUCTION
Adrenocortical carcinoma (ACC) is one of the most malignant endocrine tumors. 1,2 ACC occurs infrequently, with an incidence of 2 cases per million persons per year.1,3-9 In the United States, ACC accounts for 0.2% of cancer-related deaths. 1,2 ACC is one of the most aggressive cancers, generally carrying a poor prognosis because most patients present with large tumors and advanced disease.2 Adrenocor- tical carcinoma has a bimodal age distribution, with the first peak occurring at the age of 5 years and the second in the fourth to sixth decade of life.2,8 Adrenocortical carci- noma is most common in women, with an female/male ratio ranging from 1.5:1 to
Disclosure: The authors have nothing to disclose.
ª Division of Metabolic, Endocrine and Minimally Invasive Surgery, Department of Surgery, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1259, New York, NY 10029, USA; b Department of Surgery, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, First Ave at 16th St, Baird Hall, 16th Floor, Suite 20, New York, NY 10003, USA
* Corresponding author.
E-mail address: william.inabnet@mountsinai.org
http://dx.doi.org/10.1016/j.ecl.2015.02.008
2.5:1.2,7,10-12 These tumors are most often sporadic, but may occur in patients with hereditary syndromes such as multiple endocrine neoplasia type 1 (MEN1), Li- Fraumeni syndrome, and Beckwith-Wiedemann syndrome.13-15 The incidence is 10-fold to 15-fold higher in children in southern Brazil, where some environmental fac- tors and genetic changes have been identified in the pathogenesis of adrenocortical carcinoma. 16-18 These tumors may be hormone-secreting tumors (functional), leading to Cushing syndrome or virilization, or may be nonfunctional.
Because ACC can lead to the rapid development of locoregional invasion or distant metastasis, the 5-year survival rate varies from 32% to 50% for patients with resectable tumors. The median survival rate is less than 1 year for patients who present with meta- static disease. 19,20 Detection of tumors at an early clinical stage is imperative for curative resection. Surgical resection of ACC remains the first-line treatment and accomplishing an initial complete resection (R0) of the tumor is the most important factor for treatment success.1,2,21,22 It is important to understand that patients with ACC require a compre- hensive assessment and plan for the treatment of their disease in the preoperative, oper- ative, and postoperative periods that should be performed by a multidisciplinary group of specialists ideally with representation from radiology, nuclear medicine, endocrinology, endocrine surgery, medical oncology, pathology, and genetics.
Surgical techniques for the treatment of ACC have evolved in the last 2 decades. The classic open transabdominal or lumbar approaches have slowly been replaced by the laparoscopic approach for removal of benign adrenocortical tumors.23,24 However, although there is an ongoing debate on the role of the laparoscopic approach for the treatment of ACC, open techniques remain the approach of choice for treating most malignant primary adrenal disorders.
The main focus of this article is to provide comprehensive insight into the surgical management of ACC with an up-to-date review of surgical decision making.
MOLECULAR PATHOGENESIS
The molecular events involved in the development of sporadic ACC remain poorly un- derstood.24 As in colorectal cancer, a multistep tumor progression model has also been proposed for ACC.19 Mutations of the TP53 gene (chromosome 17p13) are the most frequent mutations reported in human cancers.25 The common finding of loss of heterozygosity (LOH) at the 17p13 locus in sporadic ACC suggests an impor- tant role of the TP53 tumor suppressor gene in the pathogenesis of sporadic ACC.26,27 Specific germline mutations have been identified in some high-risk populations, such as a subset of children from a southern Brazilian population with one of highest inci- dences of ACC, occurring 10 to 15 times more frequently than the general popula- tion.16-18 In this population, a distinct TP53 germline mutation (R337H) has been identified in up to 97% of children with adrenocortical tumors.28-30 However, only a fraction of patients with ACC harbor a mutation of TP53, indicating that there are likely to be other molecular events responsible for the pathogenesis of ACC that have not been yet identified.28-36
Other chromosomal syndromes have been strongly implicated in the pathogenesis of ACC. Alterations of the DNA methylation of 11p15, the area of abnormality in Beckwith-Wiedemann syndrome, have been implicated in the pathogenesis of ACC.37 The chromosomal locus 11p15 harbors the coding region for insulinlike growth factor (IGF)-2. Both the LOH at 11p15 and the overexpression of IGF-2 have been associated with the development of sporadic ACC.26,38,39
In contrast with the more commonly seen sporadic ACC, a subset of adrenocortical tumors are associated with hereditary cancer syndromes.15 The Li-Fraumeni
syndrome (breast cancer, soft tissue and bone sarcoma, brain tumors, and ACC) is associated with inactivating germline mutations of the TP53 tumor suppressor gene on chromosome 17p.40-42 The Beckwith-Wiedemann syndrome (Wilms tumor, neuro- blastoma, hepatoblastoma, and ACC), is associated with abnormalities in 11p15. MEN1, parathyroid, pituitary, pancreatic neuroendocrine tumors, and adrenal ade- nomas, as well as carcinoma, are associated with inactivating mutations of the MEN1 gene on chromosome 11q. Unilateral or bilateral adrenal tumors can be found in 20% to 40% of patients with MEN1; most are benign tumors, usually nonfunctional, but they can present with excess production of aldosterone or cortisol. A small subset of patients with MEN1 develop ACC.43
PRESENTATION
A careful history and physical examination should be performed to exclude signs and symptoms of pheochromocytoma, primary aldosteronism, hyperandrogenism, and Cushing syndrome. About 40% to 60% of all ACC tumors are functional and present with clinical symptoms related to hormone excess.6,8,11,20,44,45 Adults with hormone- secreting ACC usually present with features of Cushing syndrome (50%-80%) and in some cases with an associated virilization syndrome consequent to the overproduc- tion of both glucocorticoids and androgens. In some cases of severe hypercortisolism, patients present with signs and symptoms of mineralocorticoid excess as a conse- quence of glucocorticoid-mediated mineralocorticoid receptor activation.8,46 The clin- ical symptoms associated with glucocorticoid excess (weight gain, weakness, and insomnia) usually develop rapidly over a period of 3 to 6 months. Patients who have coexisting hypersecretion of adrenal androgens may not experience the typical cata- bolic effects of glucocorticoid excess (muscle and skin atrophy). A less common pre- sentation is virilization alone, but the presence of virilization in a patient with an adrenal neoplasm should increase suspicion of ACC.15 Feminization and primary aldoste- ronism occur in fewer than 10% of cases.47 Among all ACC tumors, about 20% to 30% are nonfunctioning tumors or have increased levels of adrenal steroid precursors without clinical manifestations of hormone hypersecretion. In these cases, patients usually present with clinical manifestations related to local tumor growth, such as early satiety, abdominal pain, and/or flank pain.15,48 The remaining 20% to 30% are found incidentally as an adrenal mass detected on radiographic imaging performed for unrelated clinical reasons.
In children, most patients with ACC present with virilization (84%), whereas gluco- corticoid excess alone (Cushing syndrome) or in association with other hormonal excess is uncommon.49,50
DIAGNOSTIC TOOLS AND DIFFERENTIATION BETWEEN BENIGN AND MALIGNANT ADRENOCORTICAL TUMORS Biochemical/Hormonal Evaluation
The first step on diagnosis of a patient with an adrenal tumor is to determine whether it is functional or not. In the presence of an adrenal mass suspicious for ACC, a compre- hensive hormonal evaluation is a mandatory step before surgery (Table 1).48,51 Hor- monal evaluation may help in establishing the adrenal origin of the tumor and provide tumor markers that can be useful during surveillance and follow-up after a sur- gical resection to estimate the presence of residual tumor or tumor recurrence.25,48
Adrenal carcinomas are typically inefficient steroid producers, but they secrete excessive amounts of adrenal steroid precursors because of decreased expression of several steroidogenic enzymes that may also result in diminished cortisol
| Table 1 | |
|---|---|
| Biochemical work-up of patients with suspected ACC (ENSAT recommendations) | |
| Hormonal Work-up | |
| Glucocorticoid excess (minimum 3 of 4 tests) | Dexamethasone suppression test (1 mg, 23 h) Excretion of free urinary cortisol (24-h urine) Basal cortisol (serum) Basal ACTH (plasma) |
| Sexual steroid and steroid precursors | DHEA-S (serum) 17-OH progesterone (serum) Androstenedione (serum) Testosterone (serum) 17B-estradiol (serum, only in men and postmenopausal women) |
| Mineralocorticoid excess | Potassium (serum) Aldosterone/renin ratio (if hypertension and/or hypokalemia) |
| Exclusion of pheochromocytoma (minimum 1 of 3 tests) | Metanephrines (plasma) |
Abbreviations: ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulfate; ENSAT, European Network for the Study of Adrenal Tumors.
production. Even in patients with no evidence of excess steroid production, more sen- sitive methods, such as gas chromatography/mass spectrometry, identify increased urinary metabolites of several steroids and precursors of androgens (pregnanediol, pregnanetriol, androsterone, etiocholanolone) or glucocorticoids (17-hydroxyproes- terone, tetrahydro-11-deoxycortisol, cortisol, 6-hydroxy-cortisol, tetrahydrocortisol, and alpha-cortol); this is different from cortisol-secreting adenomas, which produce cortisol but do not produce high levels of adrenal steroid precursors or adrenal androgens.52 Low serum aldosterone concentrations, but normal or high serum or urinary concentrations of aldosterone precursors (ie, deoxycorticosterone, 18- hydroxydeoxycorticosterone, corticosterone, 18-hydroxycorticosterone, tetrahydro- 11-deoxycorticosterone [THDOC], and 5 alpha-THDOC) are found in most adrenal carcinomas, but not in adrenal adenomas. 52
It is also mandatory to rule out the presence of a pheochromocytoma by determina- tion of metanephrines in plasma and/or urine before attempting resection of any adre- nal mass, and also to obtain plasma aldosterone and renin levels in patients with hypertension and/or hypokalemia.
Imaging
On imaging studies, both the size and appearance are important in distinguishing benign from malignant adrenal disorders. Computed tomography (CT) and magnetic resonance imaging (MRI) both contribute to the characterization of adrenal masses (Figs. 1 and 2).53-55 These studies are also important for determining resectability and the relationship to adjacent structures. Suspicious features to consider at the time of evaluation are tumor size, heterogeneity, the presence of tumor calcification or central necrosis, tumor infiltration into surrounding tissue or invasion into organs, and functionality of the tumor. Malignant adrenocortical tumors are usually large with a median size of 13 cm (range, 8-29 cm), as reported in a large national cancer registry study.2 On unenhanced CT imaging, most ACC has a washout of less than 50% and an attenuation of greater than 30 Hounsfield units, indicating low lipid
FOV 38.0cm IND/+
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content.17 The most common sites of distant spread for ACC are the liver, lungs, lymph nodes, and bone (see Fig. 2).8,56 For this reason, CT imaging of the chest and liver is typically included in the staging work-up if ACC is suspected based on the imaging evaluation or clinical presentation.
In a similar way, ACC most frequently presents as a large heterogeneous lesion with high intensity on T2-weighted images on MRI (see Fig. 2).53 Similar features can also
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be seen with pheochromocytoma, underscoring the need for biochemical assessment combined with radiologic evaluation. MRI/magnetic resonance angiography is the best method to determine invasion into adjacent organs and also the presence of tumor thrombosis (see Fig. 2).
PET scanning with fluorodeoxyglucose (FDG) is of value for identifying unilateral ad- renal tumors with a high index of suspicion for malignancy as well as for determining the presence and extent of metastatic disease.57-61 Although PET is more sensitive than CT or radiographic bone scans for distant metastases in a variety of clinical set- tings, false-negatives are possible and careful interpretation should be undertaken, especially when analyzing small lesions.58 Furthermore, FDG-PET helps to differen- tiate benign from malignant lesions but it does not distinguish between adrenocortical or nonadrenocortical lesions (eg, metastases or adrenocortical carcinoma).62
The combination of PET-CT imaging improves the performance of PET and can also be useful for diagnosis of ACC, but it can be nonspecific in differentiating ACC from adenomas or pheochromocytoma.55 With PET-CT, adrenal adenomas can be better differentiated from nonadenomas using a combination of CT attenuation measure- ments plus the intensity of FDG uptake. 63-65
Other alternative PET scan tracers are under investigation.62,66 Metomidate is the most widely used because it binds with high specificity and affinity to CYP11B (cyto- chrome P450, family 11, subfamily B) enzymes of the adrenal cortex. Because these enzymes are exclusively expressed in adrenocortical cells, uptake of labeled metomi- date tracers has been shown to be highly specific for adrenocortical neoplasia versus pheochromocytomas or metastases.62
Role of Fine-Needle Aspiration Biopsy
Consensus has not been reached on the use of fine-needle aspiration (FNA) for the diagnosis of ACC.53,54 FNA biopsies are of limited benefit in the evaluation of primary adrenocortical tumors because differentiation between benign and malignant tumors cannot be accurately established with needle biopsy alone. The only definitive diag- nostic criterion for a malignant primary adrenocortical tumor is distant metastasis and/or the presence of local invasion. However, FNA can help distinguish a primary adrenal tumor from a metastatic lesion (usually in patients with known, advanced ma- lignancies) or infectious/infiltrative causes.53,67,68 However, if there is a high index of suspicion that an adrenal mass is ACC, FNA is generally discouraged because of the possibility of disrupting the tumor capsule or seeding the needle track.69 If FNA is undertaken, it is essential that a diagnosis of pheochromocytoma be excluded with plasma metanephrines before the biopsy.
TREATMENT
Role of Preoperative Hormonal Therapy for Adrenocortical Carcinoma
According to the medical guidelines of the American Association of Endocrine Sur- geons for the management of adrenal tumors, all patients suspected of having ACC should undergo biochemical testing to identify hormonal abnormalities and to deter- mine whether the patient requires steroid replacement in cases of hypercortisolism.51 Preoperative preparation is essential in patients with hypercortisolism. Depending on the functionality and hormonal characteristics, the contralateral gland may be sup- pressed, resulting in atrophy and subsequent adrenal insufficiency once the tumor has been removed. Current recommendations suggest that patients with clinical or subclinical Cushing syndrome be treated with 50 mg of intravenous hydrocortisone before the induction of anesthesia and 50 mg every 6 hours for 24 hours.70 The
dose of hydrocortisone should be then tapered by half per day until it is discontinued or a maintenance level has been reached. Assuming that only 1 adrenal gland has been surgically resected, the duration of the steroid therapy depends on the time to recovery of the hypothalamic-pituitary-adrenal axis, which can take up to 2 years in some cases.71
Surgical Treatment
Open adrenalectomy
Surgical resection remains the first-line treatment of ACC. Depending on tumor stag- ing, there are different modalities and treatments. Most patients with a presumed localized ACC should undergo surgical resection because surgery is the only effective modality of treatment.72 Because complete resection is the only curative option for localized disease, special care should be taken when dissecting the tumor margins to accomplish a complete R0 resection without violation of the tumor capsule. A com- plete surgical resection can be accomplished in those patients with potentially resect- able disease stage classification (European Network for the Study of Adrenal Tumors [ENSAT] stage I-III; Tables 2 and 3). For potentially resectable tumors invading adja- cent organs, surgery often needs to be extensive, with en bloc resection of involved organs such as the kidney, liver, spleen, pancreas, stomach, and colon.1 Intracaval extension or tumor thrombus (see Fig. 2), which should be looked for on preoperative imaging, is not a contraindication to surgery; these findings may require cardiothoracic or subspecialty surgery collaboration and the use of cardiopulmonary bypass.73
ACC often spreads via lymphatic drainage. A benefit for routine lymphadenectomy during adrenalectomy was suggested in a report from the German ACC Study Group of 283 patients with completely resected ACC.74 There was a significantly reduced risk for tumor recurrence and disease-related death in patients who underwent lymphade- nectomy versus those who did not.
Although resection is technically possible for most patients with stage I to III dis- ease, it is not curative for many, presumably because occult micrometastases are
| Table 2 TNM (tumor, node, metastasis) staging system for ACC | |
| Primary Tumor (T) | |
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| T1 | Tumor <5cm in greatest dimension, no extra-adrenal invasion |
| T2 | Tumor >5 cm in greatest dimension, no extra-adrenal invasion |
| T3 | Tumor of any size with local invasion (periadrenal tissue), but not invading adjacent organs |
| T4 | Tumor of any size with invasion of adjacent organs (kidney, diaphragm, great vessels, pancreas, spleen, liver) |
| Regional Lymph Nodes (N) | |
| NX | Regional lymph nodes cannot be assessed |
| N0 | No regional lymph node metastasis |
| N1 | Metastasis in regional lymph nodes |
| Distant Metastasis (M) | |
| M0 | No distant metastasis |
| M1 | Distant metastasis |
| Table 3 Comparison of UICC/WHO and ENSAT staging classification of ACC | ||
|---|---|---|
| Stage | UICC/WHO | ENSAT |
| I | T1, N0, M0 | T1, N0, M0 |
| II | T2, N0, M0 | T2, N0, M0 |
| III | T3, N0, M0 | T3-4, NO, MO |
| T1-2, N1, MO | T1-4, N1, MO | |
| IV | T3, N1, M0 T4, NO-1, MO Any M1 | Any M1 |
Abbreviations: UICC, Union Internationale Contre le Cancer; WHO, World Health Organization.
present at the time of initial presentation, even with stage I disease.1,6,75 As an example, in a single-center report of 202 consecutive cases of ACC, 40% of patients with stage I to III disease developed distant metastasis 2 years after diagnosis (27%, 46%, and 63% of patients with stage I, II, and III disease, respectively).56
Laparoscopic adrenalectomy
Laparoscopic adrenalectomy has largely replaced open techniques for the manage- ment of benign adrenal disorders, and laparoscopic removal of even large adrenal tu- mors can be performed safely by experienced surgeons.76 However, debate still exists on the role of laparoscopic resection for ACC. Current guidelines on the surgical man- agement of ACC clearly support open resection for known cases of ACC. Several retrospective studies have shown more frequent or earlier recurrences and a shorter disease-free survival when a laparoscopic approach is used for management of ACC.77-79 In one study of 153 patients who underwent open adrenalectomy versus 6 laparoscopic resections, peritoneal carcinomatosis was observed in 8% of the pa- tients with open resection in contrast with the development of carcinomatosis in 100% of patients undergoing laparoscopic resection.77 In contrast, other studies have shown that the laparoscopic approach had comparable outcomes compared with open adrenalectomy in terms of oncologic outcomes, particularly for tumors up to 10 cm.80-85 Nonetheless, current guidelines do not recommend a laparoscopic approach for known or highly suspected ACC.51,77,78
PATHOLOGY AND STAGING
The pathologic diagnosis of ACC is frequently challenging. The distinction between benign and malignant adrenocortical tumors should only be made by pathologists experienced in using the microscopic Weiss criteria (Box 1).71,86 The only definitive diagnostic criterion for a malignant adrenocortical tumor is distant metastasis or the presence of local invasion. To date, the Weiss criteria are the most commonly used histopathologic system to determine adrenocortical malignancy.71,86 In addition to the classic microscopic evaluation of ACC, other immunohistochemical markers have been proposed (Ki-67 proliferation index, TP53, IGF-2, cyclin E) but were not suf- ficiently discriminatory in distinguishing ACC from benign adrenal disorders.70
Although the best staging system for ACC is evolving, a variety of staging systems have been used for ACC.20,37,45,87 The TNM (tumor, node, metastasis) staging system from the American Joint Commission on Cancer (AJCC)/International Union Against Cancer (UICC) (see Tables 2 and 3) is widely used but a new staging system proposed by ENSAT has gained popularity (see Table 3).73 The ENSAT staging system has
Box 1
Histopathologic features included in the Weiss criteria for evaluation of ACC
· Nuclear grade 3 to 4
· Mitotic rate greater than 6/50 high-power fields
. Less than 25% clear tumor cells in cytoplasm
. Atypical mitoses
· Diffuse architecture
· Confluent necrosis
· Venous invasion
· Sinusoidal invasion
· Capsular invasion
On microscopic evaluation, the diagnosis of ACC is made with a score greater than or equal to 3, whereas a tumor with a score of 2 is of uncertain malignancy.
better prognostic stratification restricting stage IV tumors to patients with distant me- tastases. The superiority of the ENSAT staging system compared with the 2004 UICC/ AJCC classification to determine prognosis of ACC was confirmed in an independent cohort study of 573 cases. 69
POSTOPERATIVE MANAGEMENT Therapeutic Agents for Hormonal Control
Adrenal hormonal function should be closely monitored in patients with ACC because patients may develop either adrenal insufficiency (caused by surgery or mitotane) or excess cortisol secretion (caused by persistent or recurrent tumor) in the perioperative period. In patients with hypercortisolism the administration of a specific adrenal enzyme inhibitor is often required. Controlling hypercortisolism is critical to avoid chemotherapy-induced or hypercortisolism-induced complications, such as immunosuppression-related infections or even death, from these endocrine complica- tions rather than from tumor burden.
Metyrapone is a commonly used drug in patients with ACC and hypercortisolism. Ketoconazole is effective in benign adrenal disease, but is rarely effective to control the hypercortisolism in ACC. With the use of metyrapone, eucortisolemia can be achieved within a week. If eucortisolism is not achieved with metyrapone, a combina- tion therapy with ketoconazole and mitotane can be used. A starting dosage of metyr- apone 250 mg 4 times daily is recommended. This dosage can then be increased up to 6 g/d. If there is not appropriate response with metyrapone alone or it is not tolerated, ketoconazole is started at 200 mg 3 times per day, increasing daily as needed to 400 mg 3 times per day. Their effect can be assessed within a few days by measuring 24-hour urine cortisol levels. A combination of both drugs and mitotane may be neces- sary to achieve adequate control in some circumstances. In severe uncontrolled cases, addition of mifepristone, a glucocorticoid receptor antagonist, can be benefi- cial.88 In patients who are unable to take drugs orally, intravenous etomidate (which blocks 11-beta-hydroxylase) can be used at a low dosage of 0.3 mg/kg/h. The use of etomidate requires a specialized team and appropriate hemodynamic monitoring.
Adrenal insufficiency is initially managed using replacement with intravenous hydro- cortisone and then oral glucocorticoids for maintenance. Mitotane induces the
metabolism of glucocorticoids, so higher-than-usual replacement doses are needed in patients receiving mitotane therapy. Aldosterone deficiency is replaced with the addition of fludrocortisone (0.1-0.3 mg daily) and adjusted to restore normal blood pressure and serum levels of potassium and renin. A small percentage of adult pa- tients with ACC and a high percentage of pediatric patients with ACC present with virilization with/without hypercortisolism. Virilization is best treated with specific androgen blockage with androgen receptor inhibitors (bicalutamide at 50 mg/d) or 5-alpha reductase inhibition (finasteride at 5 mg/d).
Rare estrogen-producing ACC tumors can be treated with any of the antiestrogen therapies, including tamoxifen or aromatase inhibitors.
Mitotane Therapy
Mitotane is an adrenocorticolytic/adrenal enzyme inhibitor drug that has efficacy in pa- tients with ACC.89 It has been used in the adjuvant setting, for primary therapy for unresectable disease (stage IV), and for the treatment of disease recurrence, either alone or in combination with other cytotoxic agents.
Data showing the benefit of routine postoperative (adjuvant) administration of mito- tane have been mixed, in large part because of the rarity of ACC and the lack of pro- spective randomized clinical trials. Although several uncontrolled reports suggest that adjuvant mitotane may delay or prevent recurrence in patients undergoing complete primary resection for nonmetastatic disease,90-96 others have failed to show any benefit in terms of disease-free or overall survival. 11,20,44-46,97-99
Despite the ongoing debate about who should be treated with mitotane, its use is generally recommended in those patients with metastatic disease or advanced local- ized disease in which a high recurrence rate is expected. The decision to use mitotane should be made on a case-by-case basis considering critical prognostic factors such as completeness of resection, proliferation rate, and accurate tumor staging to identify the high-risk patients with increased chances of tumor recurrence. 100-102
Other Chemotherapy Protocols
It remains unknown whether chemotherapy alone or in combination with mitotane is more effective than adjuvant mitotane alone.
Adjuvant chemotherapy plus mitotane
A few prospective trials have explored combination regimens that contain mitotane. Although no chemotherapy regimen has been shown to improve overall survival in pa- tients with advanced ACC, some of the more encouraging results have been with the combination of etoposide, doxorubicin, and cisplatin plus mitotane. 103,104
Results with other chemotherapy drugs combined with mitotane are less promising. 105-107
Chemotherapy without mitotane
Although they are frequently used, single agents such as cisplatin, cyclophosphamide, or doxorubicin are associated with poor response rates.108,109 The overall result of chemotherapy protocols without the use of mitotane is discouraging. 108-111
Radiation Therapy
It was thought that malignant adrenocortical tumors were radioresistant tumors; how- ever, this is not likely to be true, at least in light of most recent studies. 112-114 Although there are no randomized trials testing the efficacy of adjuvant radiotherapy (RT) in pa- tients with resected ACC, some support a benefit in certain patients who are at high risk for a local recurrence.112,113 However, in a recent retrospective study of 16
patients with ACC who had undergone either surgery followed by adjuvant RT or sur- gery alone, the rate of local recurrence was not significantly reduced by adjuvant RT.114 In addition, even in the studies that show an apparent benefit of adjuvant RT in decreasing local recurrences, neither disease-free nor overall survival was signifi- cantly better in irradiated patients. 112,113
The currently available data in the literature support the palliative benefit of RT for unresectable local tumor that is causing local symptoms, or for distant symptomatic metastases, such as in bone, brain, and vena cava. 1,112,115,116
Additional Surgery
Adrenocortical carcinoma with locally advanced, recurrent or metastatic disease Locally advanced, recurrent, or metastatic ACC has a dismal prognosis. However, in those cases in which the tumor cannot be removed entirely, or in those cases with recurrent or distant metastatic disease, many studies have advocated that tumor debulking may have an impact on survival and at least some reports suggest that long-term survival rates are higher among patients who undergo resection of recurrent or metastatic disease, 1,11,21,44,87,117-119 although others disagree. 46
In a study of 47 patients with ACC undergoing resection for locally recurrent or distant metastatic disease, the 5-year survival rates for patients with completely and incompletely resected locally recurrent disease were 57% and 0%, respectively.119 Similar outcomes were reported in a study of 57 patients undergoing different surgical procedures for recurrent or metastatic ACC, with a 5-year survival of 41%, and median survival significantly longer for those with a disease-free interval greater than 12 months (6.6 vs 1.7 years). Another study of 28 patients undergoing resection for liver metastases from ACC (25 isolated, 3 with extrahepatic metastases), the 5-year survival rate was 39%.118 The investigators concluded that, in selected patients with ACC liver metastases, resection is associated with an improvement in long- term survival, although it is not curative.
If complete resection is feasible, an aggressive surgical approach to locally recur- rent disease, with the aim of achieving negative surgical margins, should be under- taken.119-121 Resection may also be considered in the rare patients who present with limited, potentially resectable hepatic or pulmonary metastases. Resection of locally recurrent disease may also be indicated for patients in whom surgery is able to remove most, but not all, of the tumor burden or decrease severe hypercortisolism that is otherwise difficult to control.4 This approach should be limited to selected pa- tients with uncontrollable symptomatic hormone excess or those who are in imminent danger from organ invasion/compression.
Tumor debulking of nonresectable ACC should be considered on a case-by-case basis, taking into consideration the overall patient condition, tumor biology, rate of progression, and the histologic grade.1 In those cases of invasive disease and tumors with high hormonal production, the patients may benefit from a palliative tumor reduc- tion. 44,122 However, in some patients the presence of unresectable high-grade tumors may limit their treatment to palliation with medical management.8
Surveillance Strategy
For patients with a completely resected steroid-producing ACC, patients should be monitored every 3 months for 2 years with steroid tumor markers such as cortisol, de- hydroepiandrosterone sulfate, androstenedione, testosterone, estradiol, or mineralo- corticoid based on the steroid profile of the initial tumor. Careful interpretation of biochemical values should be undertaken in those patients receiving mitotane therapy because it alters steroid hormone levels and metabolism. The 24-hour urinary free
cortisol excretion remains as the best index of cortisol production currently avail- able. 123 Plasma adrenocorticotropic hormone (ACTH) levels may be used to measure reduction in cortisol (ACTH becomes detectable) and possible adrenal insufficiency (ACTH level increases beyond normal values).
PROGNOSIS
The overall survival for ACC is poor. It is estimated that the 5-year survival rate is approximately 32% to 50% for patients with resectable tumors and the median sur- vival rate is less than 1 year for those with metastatic disease. 19,20 The most important clinical factors that determine prognosis of ACC are disease stage and completeness of resection. 8,11,20,29
Tumor staging remains one of the best prognostic tools; however, survival may differ widely for any given tumor stage because many other factors, including genetic predisposition, could influence the outcomes.
SUMMARY
The molecular events involved in the pathogenesis of ACC remain unclear in most cases. Patients with ACC or with adrenal tumors suspicious for malignancy should be managed by a multidisciplinary team. A careful and comprehensive evaluation with biochemical and imaging studies is recommended for any adrenal mass concern- ing for malignancy. The gold-standard treatment of ACC is complete surgical resec- tion with negative margins when possible. Mitotane therapy has been the mainstay of adjuvant therapy but controversy remains as to its utility in earlier stage disease. Although data are limited, there is some evidence that chemotherapy protocols can lead to extended survival in selected patients with advanced ACC.
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