Treatment of Adrenocortical Carcinoma: Contemporary Outcomes
David Y. T. Chen, MD*, R. Ernest Sosa, MD, and Douglas S. Scherr, MD
Address
*Department of Urology, New York-Presbyterian Hospital, Weill Cornell Medical Center, Starr 900, 525 East 68th Street, New York, NY 10021, USA.
E-mail: dchen@nyp.org
Current Urology Reports 2004, 5:65-72 Current Science Inc. ISSN 1527-2737 Copyright @ 2004 by Current Science Inc.
Adrenocortical carcinoma is a rare cancer that historically has been associated with poor outcome. Throughout the past decades, growing experience has allowed better understanding of the natural history and optimal manage- ment of this cancer. Advances in imaging and aggressive sur- gical therapy have raised the outlook for recently diagnosed patients. Further improvements in survival will require more effective systemic therapy.
Introduction
Adrenocortical carcinoma is a highly aggressive and malignant cancer. It has a poor prognosis because of advanced disease stage at diagnosis and a high rate of recurrence after potentially curative surgery. Recent analyses suggest a changing outcome. Patients diag- nosed and treated in recent decades have experienced improvements in survival [1,2]. This change reflects improved diagnostic techniques and supportive mea- sures, allowing for earlier disease diagnosis and more intensive therapy. This article reviews the natural his- tory of adrenocortical carcinoma and addresses current and future aspects of management.
Epidemiology
In the United States, adrenocortical carcinoma is rare, with an estimated incidence of less than two cases per 1 million people annually [3]. It can develop at any age, but shows a bimodal age distribution with a peak inci- dence in the first and the fifth decades of life. Women (children and adults) are affected more often than men [4]. There is a higher incidence in families with a tumor predisposition such as the Beckwith-Wiedemann, Li- Fraumeni, or SBLA (S, sarcoma; B, breast and brain can- cer; L, leukemia, laryngeal, and lung cancer; A, adreno- cortical carcinoma) syndromes [5].
Presentation
Adrenocortical tumors can produce corticosteroids, sex hormones, or, less commonly, mineralocorticoids, thereby causing symptoms because of endocrine excess. Even in the absence of clinical symptoms, most cases of carcinoma demonstrate some degree of hormone production during an evaluation. Children frequently are symptomatic. More than 90% of pediatric patients have clinical symptoms of a functional tumor, most commonly demonstrating viriliza- tion with or without Cushing’s syndrome [6]. In adults, approximately 70% of cases show clear evidence of hor- monal excess, with classical Cushing’s syndrome being most common and found in more than 50% of symptom- atic cases. Less common is virilization, presenting alone or concurrently with Cushing’s syndrome in 20% to 30% of patients, and a few patients demonstrate feminization or hyperaldosteronism. Of the remaining cases, elevated hor- mone levels can be identified without definite symptoms in an additional 15% to 20%; the remaining 10% to 15% will have a nonfunctional tumor [7]. In addition to symp- toms from hormone excess, a palpable abdominal mass is the most common finding of adrenocortical carcinoma, with abdominal pain, weight loss, and fever also occurring frequently [8]. In the 1980s, Hogan et al. [9] and Karakou- sis et al. [10] suggested that functional tumors exhibited better prognosis than nonfunctional tumors. Functional status of tumors may alter time to diagnosis because non- functional tumors may not present until they reach large size and produce secondary symptoms from mass effect or metastatic disease [5]. However, later and larger studies have demonstrated that functional status has no impact on survival [11-14] and the average size of functional or non- functional tumors is not significantly different [8,14]. Ken- drick et al. [2] reviewed the Mayo Clinic experience of adrenocortical carcinoma in 58 patients treated since 1980. They found that nonfunctional tumors carried favor- able prognosis compared with functional tumors in univariate and multivariate analysis and it was one predic- tor of longer survival in their study. One possible explana- tion for this finding is that a larger number of tumors now may be identified as incidental and nonfunctional lesions because of the increased use of body imaging. Overall, a larger number of incidental adrenal lesions are found today compared with the pre-computed tomography (CT) scan era. Mantero et al. [15.] have reviewed more than 1000 patients collected from 26 centers throughout Italy as
| Stage | |
|---|---|
| I | Tumor ≤5 cm confined to adrenal; no nodal or distant metastasis |
| II | Tumor > 5 cm confined to adrenal; no nodal or distant metastasis |
| III | Tumor is any size and extends beyond adrenal, but not into adjacent organs or positive regional lymph nodes with no distant metastasis |
| IV | Tumor is any size and extends beyond adrenal, but not into adjacent organs and positive regional lymph nodes with no distant metastasis |
| Tumor | |
| T1 | Tumor ≤5 cm confined to adrenal |
| T2 | Tumor > 5 cm confined to adrenal |
| T3 | Tumor is any size and extends beyond adrenal, but not into adjacent organs, with no negative regional lymph nodes and no metastases |
| T4 Lymph nodes | Tumor is any size and invades adjacent organs, with positive regional lymph nodes and no distant metastases |
| N0 | Negative regional lymph nodes |
| N1 Metastases | Positive regional lymph nodes |
| M0 | No distant metastases |
| M1 | Positive distant metastases |
| Adapted from Norton and Le [19]. | |
part of a national survey of incidental adrenal masses con- ducted by the Italian Society of Endocrinology. All of the patients were diagnosed with an incidental adrenal mass between 1980 and 1995, were approximately 50% before 1990 and 50% after 1990, and all underwent assessment with high-resolution abdominal imaging and full hor- monal evaluation. Eighty-five percent of the lesions were nonfunctional, with subclinical Cushing’s syndrome being the most common functional abnormality in 9%. Adrenal- ectomy subsequently was performed in 380 patients. Although cortical adenoma was the primary finding in 52%, 47 adrenocortical carcinomas also were found, com- prising 12% of resected masses. Assuming that all of the adrenal masses that were not removed were benign lesions, this series demonstrates greater than 4% frequency of pri- mary carcinoma in incidental adrenal masses, suggesting that adrenocortical carcinoma is not a rare finding in this clinical scenario. Other smaller series also have found a similar frequency of incidental adrenocortical carcinoma, ranging from 2% to 9% [16,17]. However, these studies have not demonstrated that carcinoma diagnosed in inci- dental lesions presents at a lower stage at diagnosis or results in improved patient outcome.
Staging
Staging of adrenocortical carcinoma is assigned according to stage criteria based on the system popularized by Mac- Farlane [18] (Table 1). Stage I or II disease is localized to the adrenal gland, the most favorable for complete resec- tion, and predicts the best long-term survival after curative surgery. In contrast, stage III or IV disease involves spread beyond the adrenal gland that may be amenable to surgical excision with associated adjacent tissue, depending on the
location of tumor invasion and organ structures involved. Unfortunately, most patients present with advanced dis- ease (Table 2), with approximately 70% having stage III or IV disease at the time of diagnosis; advanced stage is inversely correlated with survival [4]. Children with adrenocortical carcinoma generally have a more favorable prognosis with higher overall survival, partly resulting from a diagnosis at a lower stage. In contrast to adults, most children present with stage I or II disease, with most cases being functional and virilizing [6].
Diagnosis
Evaluation of suspected adrenocortical carcinoma includes hormonal evaluation to determine functional or nonfunc- tional status and body imaging to radiographically charac- terize the adrenal lesion.
Hormonal evaluation
The goal of hormonal evaluation is to recognize abnormal- ities that require treatment and minimize morbidity from secondary endocrine excess. Functional status of adrenal tumors can be dynamic and re-evaluation is warranted in the setting of a clinical change. Clinical presentation of each patient will direct the specific assessment of biochem- ical parameters, but a minimal endocrine evaluation should be performed in every patient to rule out occult abnormalities. Hypercortisolemia is the most common endocrinopathy, causing overt or subclinical Cushing’s syndrome, and this is best measured by 24-hour urinary- free cortisol [27]. Morning and evening serum cortisol measurements will confirm a hypersecreting adrenal lesion if diurnal variation is absent. Simultaneous serum cortisol and adrenocorticotropic hormone measurements will
| Study | Group | Year | Number | Stage III/IV at diagnosis | Complete resection | Recurrence | Overall 5-year survival rate | resection 5-year Complete survival rate | resection 5-year Incomplete survival rate |
|---|---|---|---|---|---|---|---|---|---|
| King and Lack [8] | Armed forces | 1979 | 49 | 34 (69%) | 21 (43%) | 10 (48%) | 22% | 43% | 0% |
| Bodie et al. [1 ]] | Cleveland Clinic | 1989 | 82 | 42 (52%) | 46 (56%) | 26 (57%) | 25% | 44% | 6% |
| Venkatesh et al. [20] | MD Anderson | 1989 | 110 | 72 (65%) | 50 (45%) | 29 (58%) | 23% | 42% | NR |
| Grondal et al. [21] | Sweden | 1990 | 54 | 48 (89%) | 22 (41%) | 12 (55%) | 19% | 45% | 0% |
| Soreide et al. [22] | Norwegian registry | 1991 | 99 | 63 (64%) | 51 (52%) | 42 (82%) | 16% | 62% | 0% |
| Pommier and | Memorial | 1992 | 73 | 48 (66%) | 53 (76%) | 45 (85%) | 35% | 47% | 0% |
| Brennan [23] | hospital | ||||||||
| Zografos | Roswell Park | 1994 | 53 | 40 (75%) | 15 (28%) | 15 (100%) | 19% | 38% | 0% |
| et al. [24] | |||||||||
| Haak et al. [25] | Leiden Hospital | 1994 | 96 | 38 (40%) | 47 (49%) | 38 (81%) | 27% | 49% | 9% |
| Bellantone | Italian registry | 1997 | 188 | 95 (49%) | 140 (78%) | 52 (37%) | 24% | 45% | 3% |
| et al. [26] | |||||||||
| Schulick and | Memorial | 1999 | 113 | 56 (50%) | 68 (60%) | NR | 37% | 55% | 5% |
| Brennan [13] | hospital | ||||||||
| Icard et al. [1] | French registry | 2001 | 253 | 111 (44%) | 182 (72%) | NR | 38% | 50% | 0% |
| Kendrick et al. [2] | Mayo Clinic | 2001 | 58 | 28 (48%) | 41 (71%) | 30 (73%) | 37% | 58% | NR |
NR-not reported.
confirm a pituitary-independent source of cortisol. Dexamethasone-suppression testing can additionally con- firm hypercortisolemia. After dexamethasone administra- tion, serum cortisol is suppressed to less than 5 mg/dL in control subjects. Values higher than 10 mg/dl are consis- tent with cortisol excess and lack of suppression.
Serum levels of sex hormones should be assayed to evaluate patients showing virilization or feminization and to identify asymptomatic patients. Patients who are nor- motensive with normal serum potassium do not need fur- ther evaluation for mineralocorticoid-producing tumors; however, those with hypertension and hypokalemia should undergo serum aldosterone measurement. Total urinary catecholamine and metanephrine should be evalu- ated to rule out pheochromocytoma [5].
Imaging
Computed tomography imaging is the first-line study to evaluate the adrenal glands because of overall favorable imaging quality, speed and convenience, and accurate localization of lesions. CT scanning enables determination of local tumor extent and any associated nodal or visceral spread. It provides important information regarding the possible involvement of the ipsilateral kidney and con- firming function in the contralateral kidney.[5] However, CT imaging can be limited in assessment of liver or kidney involvement and tends to overestimate the actual degree of local invasion [7]. Magnetic resonance imaging (MRI) is becoming the study of choice because of a better definition of anatomy, augmenting information obtained from CT imaging. MRI allows better resolution of tumor thrombo- sis in vessels, especially in the inferior vena cava and adre- nal and renal veins, and can better show hepatic or renal invasion. When applying specific sequences or chemical shift studies, MRI often can provide tissue characterization and distinguish between nonfunctioning adenomas, pheo- chromocytomas, and primary malignant adrenocortical carcinomas [28]. Certain CT and MRI criteria suggest adrenocortical carcinoma, including large size (> 5 cm), heterogeneous density, central areas of tumor necrosis, tumor calcification, and invasive disease as evidenced by locally invasive, nodal, or venous spread. Other modalities such as angiography or nuclear imaging may provide addi- tional information in selected patients, but, in most cases, CT or MRI is sufficient for treatment planning. CT and MRI can underestimate the true size of adrenal masses by approximately 20% when evaluating lesions bigger than 3 cm in size [29].
Treatment and Outcome Surgery
Complete surgical excision of adrenocortical carcinoma is the primary goal of treatment and offers the best chance for cure. Removal of tumor with resection of all of the vis- ible disease is indicated when possible (unresectable dis-
ease or incomplete surgical resection is associated with a uniformly poor outcome with rapid disease progression and median survival of less than 1 year) [13]. Resectabil- ity is an independent positive prognostic feature [1,13,26]. Comparing overall 5-year survival with 5-year survival after complete resection and 5-year survival after incomplete resection, multiple series in the literature show significantly improved survival rates after complete surgical resection and few long-term survivor rates with- out surgery, highlighting the limited effectiveness of non- surgical therapy. Even after complete surgical resection, local or metastatic recurrence of carcinoma is common in most cases in various series (Table 2). For patients with solitary metastasis or localized recurrence amenable to repeat resection, additional surgery has been shown to improve survival, with 5-year survival rates after resection of recurrent disease being between 50% and 57%; an inoperable recurrence results in a 5-year survival rate between 0% and 8% [13,26].
To maximize exposure and optimize the surgical resection of disease, open surgery is strongly advocated as the standard approach for every suspected malignant adrenal lesion [30,31]. A large body of literature exists supporting laparoscopic adrenalectomy as the preferred approach for small (< 5 cm) and benign adrenal lesions, regardless of functional status [32]; however, there is con- troversy regarding its use to treat malignant tumors. One concern is an increased risk of recurrence after laparo- scopic adrenalectomy compared with an open approach [31]. Laparoscopic adrenalectomy is feasible for larger and potentially malignant adrenal lesions. Hobart et al. [33] addressed the ability to replicate open surgical tech- nique and maintain oncologic surgical principles during laparoscopic adrenalectomy for large-volume masses. They reported a retrospective series of laparoscopic adrenalectomies performed for lesions averaging 8 cm and compared short-term outcomes with matched cases treated by open adrenalectomy. They found no higher operative complication rate between laparoscopic and open resection and final pathologic specimens from each group showed the same degree of en bloc resection of adrenal and periadrenal fat. In 2002, Kebebew et al. [34 .. ] evaluated laparoscopic adrenalectomy for malig- nant adrenal tumors, removing 13 adrenal metastases, six primary adrenal cancers, and two lymphomas. They suc- cessfully resected every lesion with negative surgical mar- gins, with a mean primary adrenal cancer size of 6.6 cm (range, 2.5-12 cm) and a mean metastatic adrenal tumor size of 4.8 cm (range, 1.5 to 12 cm). The most significant finding from their study was their follow-up, which showed comparable results with that of open adrenalec- tomy, with recurrence seen in 35% (seven of 20) and 65%, respectively, of patients with disease-free survival at 3.3 years of follow-up. Their report demonstrates that lap- aroscopic adrenalectomy can be effectively performed for adrenocortical carcinoma and other malignant adrenal
tumors in appropriately selected patients with no greater risk of recurrence compared with open surgery.
Medical treatment
Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlo- rophenyl) ethane, was initially described in 1960 by Ber- genstal et al. [35] to lead to tumor regression and reduce corticosteroid production in patients with adrenocorti- cal carcinoma. This is the first drug usually used in patients with metastatic or unresectable adrenocortical carcinoma and response rates range from 14% to 35% [4,11,20,26]. Mitotane was isolated as the active isomer from the insecticide dichloro-diphenyl-dichloroethane after it was observed to block cortisol synthesis and lead to adrenal atrophy and necrosis in dogs. Although case reports of complete responses to mitotane have been published [36], since then, larger studies have been unable to show improvement in survival; however, patients may demonstrate tumor regression or a reduc- tion in tumor functional activity [11,12,23]. One posi- tive study by Haak et al. [25] reported 27% responses in 55 patients, with some long-term complete remissions. The authors identified a response to mitotane only in patients having high serum levels (higher than 14 mg/ L); patients with lower levels had outcomes similar to untreated patients. They hypothesized that the lack of mitotane benefit of other studies may be caused by inad- equate serum levels. The challenge of mitotane is that it traditionally requires high daily dosages (6-10 G/d), which is poorly tolerated by most patients. When serum levels approach 5 mg/L, there are commonly associated gastrointestinal symptoms; significant neurologic symp- toms develop at serum levels higher than 15 mg/L. Rec- ognizing that traditional high daily dosing has significant side effects and poor compliance, Terzolo et al. [37] published a prospective study of a low-dose mitotane daily regimen (1-2 G/d), using the fact that mitotane accumulates in adipose tissue. The study was intended as a feasibility trial of the dosing regimen. In five of their eight patients, the authors noted successful ongoing long-term (8 to 40 months) treatment with good drug tolerance, minimal toxicity, and adequate therapeutic levels; mitotane therapy was stopped in only one patient because of side effects. Although the study was not meant to evaluate mitotane activity, stable dis- ease was found in four patients at the last follow-up and it was speculated that low daily-dose therapy may be superior to traditional dosing because of greater patient compliance with maintained therapeutic drug levels. Further studies are needed to demonstrate mitotane activity when this low daily-dose schedule is applied.
Although mitotane is considered to be the most effec- tive systemic agent based on retrospective studies, no pro- spective randomized trials exist. Because of the high rate of recurrence of adrenocortical cancer, mitotane also has been tried in the adjuvant setting after surgery in hopes of reduc-
ing the recurrence rate. In this application, in contrast to its presumed benefit for unresectable disease, multiple groups have shown no reduction in recurrence and no improve- ment in survival with surgery after mitotane compared with surgery alone [1,11,12,23].
Mitotane frequently causes adrenal insufficiency. Corti- costeroid replacement is indicated while the patient is receiving mitotane therapy (adrenal insufficiency has been confused for mitotane toxicity and mitotane has been stopped inappropriately) [37].
Other traditional cytotoxic chemotherapy agents have been tried in single- and multiagent studies, most com- monly based on cisplatin alone or in combination with other agents. Their responses generally have been partial and, overall, less than 30% in the several small series reported no clear advantage of any particular regimen com- pared with mitotane. Because of the number of patients who present with metastatic or unresectable disease, other more active agents are needed.
Radiation therapy
Markoe et al. [38] described radiation treatment of adreno- cortical carcinoma and possible benefit in the adjuvant set- ting after surgery, but no other studies have documented its effectiveness. The primary use of radiation therapy has been to treat symptomatic metastatic or unresectable primary dis- ease and it is effective at palliation in this setting [39].
Other treatments
Focal tissue ablative therapy may have a role for patients who are not candidates for surgery, allowing treatment of disease with less treatment risk. It also may be beneficial for patients with recurrent or symptomatic disease for whom additional surgery may be of unclear benefit. Cryo- surgery and radiofrequency thermal ablation have been used for treatment in other soft tissue malignancies and in hepatic metastases and recent studies have shown their fea- sibility for adrenal lesions [40,41]. As growing experience in these approaches develops, it is possible they may be used as an alternative to surgery in patients with small pri- mary or localized recurrent adrenocortical carcinoma. However, no long-term outcomes from these treatments exist to recommend them over resection for patients who are otherwise candidates for surgery. Angioembolization or chemoablation of adrenocortical carcinoma also have been described in case reports, mainly for palliation in inoperable adrenal lesions or in patients who could not tolerate surgery [42].
Pathologic Features and Prognosis
The only definite factor to differentiate benign from malig- nant adrenocortical tumors is nodal or distant metastases. Certain histopathologic criteria have been recognized that are suggestive of carcinoma, such as tumor weight higher than 100 G, tumor necrosis, high nuclear grade, atypical
mitotic figures, high mitotic rate, vascular, capsular, or sinusoidal invasion, fibrous bands, or less than 25% clear cytoplasm [43,44], but no one of these features is diagnos- tic. Although size generally has been used as a primary cor- relate of malignant behavior, it can be misleading of the true diagnosis because large adrenal tumors lacking inva- sive features or cellular atypia have been described [21]. Likewise, not every small adrenal tumor is benign, with 13.5% of a recent series of adrenocortical carcinomas noted as being less than 5 cm in size [45]. Weiss et al. [44,46] applied several of the previously mentioned crite- ria to diagnosis and showed that less aggressive and non- metastasizing tumors had fewer than two histologic features; clinically malignant tumors showed three or more features. Some of these characteristics have further shown to be of significance in predicting prognosis. Mitotic rate has been evaluated by several investigators and can serve as a strong independent predictor for overall and disease-free survival [44,46,47.]. To stratify patients as having high- grade or low-grade cancer, Stojadinovic et al. [47·] identi- fied six histopathologic features significantly associated with an adverse outcome and worse disease-specific sur- vival: venous invasion, capsular invasion, adjacent organ invasion, tumor necrosis, mitotic rate, and atypical mitosis. Patients with two or fewer features had a 5-year disease- specific survival of 83.5% compared with those having three or four features (36.8%) or more than four features (8.6%). They also examined molecular markers Ki-67, p53, and mdm-2, but did not find any similar predictive value correlating expression of markers with patient outcome. With better identification of high-risk patients by these cri- teria, it may be possible to tailor more aggressive treatment or surveillance protocols to patients with high-grade can- cers to improve outcomes. These associations between his- topathologic features and outcome have not shown to correlate in pediatric cases of adrenocortical carcinoma. In children, tumors with very malignant features often will have a benign course, demonstrating a different natural history for pediatric cases versus adult cases [48.].
Other Issues Fine needle aspiration cytology
There are few indications to obtain cytology of suspected malignant adrenal lesions. For primary adrenal tumors, there is limited ability to distinguish between benign and malignant lesions by fine needle aspiration (FNA). In the event of adrenocortical carcinoma, the procedure poten- tially can seed tumor cells and increase the risk of recur- rence after a definitive resection [19]. For this scenario, laparoscopic adrenalectomy offers a diagnostic and defini- tive treatment that is less invasive and an acceptable alter- native to open adrenalectomy.
Adrenal masses may be found in patients with a history of extra-adrenal malignancy undergoing surveillance. FNA can confirm metastatic disease, but there is a roughly 20%
false negative rate and FNA results may not alter clinical management. Positive FNA cytology should lead to adrenalectomy if the patient has no other evidence of dis- ease and is otherwise a good surgical candidate (see next section). Approximately 50% of adrenal masses in patients with a history of extra-adrenal malignancy are unrelated to their previous cancer. Most of these adrenal masses are tumors that demand excision [51]. Therefore, in the patient with an adrenal mass and a history of cancer, FNA is help- ful for cases of adrenal metastasis that would be treated with chemotherapy (eg, lymphoma), but otherwise the adrenal mass may be treated best with upfront laparo- scopic adrenalectomy.
Adrenal metastasis
Metastatic lesions to the adrenal develop most commonly from the lung, kidney, stomach, liver, and melanoma, but other sites of origin have been reported. In selected cases of isolated adrenal metastasis, surgical resection can result in long-term survival [49,50]. A laparoscopic approach has been shown to be effective, especially because the mean metastatic tumor size tends to be smaller than that of pri- mary adrenocortical carcinoma and invasion outside of the gland is not seen [34 .. ]. However, despite a history of malignancy, when an adrenal mass is identified, it does not represent metastatic disease in approximately 50% of the cases. In this context, the adrenal mass cannot be assumed to be a metastasis; therefore, full evaluation with hormonal and imaging studies is warranted [51].
Recent Outcomes
Despite the overall poor prognosis and lack of new treat- ment options for adrenocortical carcinoma, two studies highlight our improved understanding of the natural his- tory and management of adrenocortical carcinoma.
Kendrick et al. [2] reviewed all of the patients with adrenocortical carcinoma who were treated surgically at the Mayo Clinic between 1980 and 1996 and compared their outcomes with a similar cohort of patients treated between 1960 and 1980. Comparing the groups, despite no change in mean tumor size (12.5 cm), they found a sig- nificant reduction in patients having stage III or IV tumors (48% versus 66%), with an associated increase in the rate of patients having curative surgical resection (71% versus 50%) in patients treated more recently. Consequently, overall 5-year survival more than doubled to 37% from 16% and, in comparison with other quoted outcomes, it equals the highest numbers documented (Table 2). Their improvement in results underscores the importance of patient evaluation and selection, which has improved over time with advances in high-resolution imaging. The out- come of their earlier series is comparable with other series of patients from the past, reflecting the inherent limita- tions of staging adrenocortical carcinoma that existed in the pre-CT era.
Much of the improved outcome for their later patients can be attributed to better patient selection. The identified patients presented at an earlier stage and had a higher probability of curative resection. Addi- tionally, these patients benefited from repeated resec- tion. Surgical opinion now recognizes that resection of recurrence improves survival; in contrast, no patient in their former series underwent a second operation when there was cancer recurrence.
Icard et al. [1] retrospectively reviewed outcomes of 253 patients treated for adrenocortical carcinoma between 1978 and 1997 by the French Association for Endocrine Surgery. The significant factors having favorable prognostic significance in multivariate analysis included complete curative resection, early stage at diagnosis (stage I or II), and diagnosis and treatment in 1988 or later. Unlike the Mayo Clinic data, the improved survival with more recent diagnosis was not explained by tumor stage or rate of cura- tive surgery, which was equal during both time periods. The authors speculate that improvement in survival in the more recent group was caused by better perioperative care, from anesthesiology and intensive care unit experience, and lower operative mortality, which decreased over time. A larger percentage of stage-IV patients also received mito- tane therapy in the recent period compared with the earlier period and had higher survival rates. However, an impor- tant point of this report is that only slight improvement resulted after optimization of the current surgical and medical management of adrenocortical carcinoma. Although the patients who received a later diagnosis had a better prognosis than those treated before 1988, the improvement in outcome is not as great as has occurred in the past, which is illustrated by the Mayo Clinic study. These two studies demonstrate how outcomes for adreno- cortical carcinoma changed after the advent of cross-sec- tional imaging and have improved with refinements in surgical therapy, but are likely to remain less than 50% until more efficacious medical therapy is available. Although 5-year survival rates after curative resection can be higher than 50%, a significant improvement in overall survival likely will not occur until there is another new development, such as allowing earlier diagnosis or offering superior surgical or medical treatment.
Conclusions
Adrenocortical carcinoma traditionally has been considered a rare, poorly responsive malignant tumor, but recent stud- ies show that it may not be as uncommon or have as poor an outcome. Modern imaging allows better preoperative staging and surgical planning and refinements in surgical and medical therapies offer many patients the potential for long-term survival. A better understanding of prognostic fea- tures allows identification of high-grade and low-grade dis- ease. Future improvements in outcome will require earlier diagnosis and more effective medical therapies.
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