CLINICAL REVIEW: Adrenocortical Carcinoma: Clinical Update
Bruno Allolio and Martin Fassnacht
Endocrinology and Diabetes Unit, Department of Medicine I, University Hospital Wuerzburg, 97080 Wuerzburg, Germany
Context: Adrenocortical carcinoma (ACC) is a rare and heteroge- neous malignancy with incompletely understood pathogenesis and poor prognosis. Patients present with hormone excess (e.g. viriliza- tion, Cushing’s syndrome) or a local mass effect (median tumor size at diagnosis > 10 cm). This paper reviews current diagnostic and therapeutic strategies in ACC.
Evidence Acquisition: Original articles and reviews were identified using a PubMed search strategy (http://www.ncbi.nlm.nih.gov/ entrez/query.fcgi) covering the time period up until November 2005. The following search terms were used in varying combinations: ad- renal, adrenocortical, cancer, carcinoma, tumor, diagnosis, imaging, treatment, radiotherapy, mitotane, cytotoxic, surgery.
Evidence synthesis: Tumors typically appear inhomogeneous in both computerized tomography and magnetic resonance imaging with necroses and irregular borders and differ from benign adenomas by their low fat content. Hormonal analysis reveals evidence of steroid hormone secretion by the tumor in the majority of cases, even in seemingly hormonally inactive lesions. Histopathology is crucial for the diagnosis of malignancy and may also provide important prog- nostic information. In stages I-III open surgery by an expert surgeon
aiming at an R0 resection is the treatment of choice. Local recurrence is frequent, particularly after violation of the tumor capsule. Surgery also plays a role in local tumor recurrence and metastatic disease. In patients not amenable to surgery, mitotane (alone or in combination with cytotoxic drugs) remains the treatment of choice. Monitoring of drug levels (therapeutic range 14-20 mg/liter) is mandatory for op- timum results. In advanced disease, the most promising therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane, and strep- tozotocin plus mitotane) are currently being compared in an inter- national phase III trial (www.firm-act.org). Adjuvant treatment options after complete tumor removal (e.g. mitotane, radiotherapy) are urgently needed because postoperative disease-free survival at 5 yr is only around 30%, but options have still not been convincingly established. National registries, international cooperations, and trials provide important new structures for patients but also for researchers aiming at systematic and continuous progress in ACC. However, future advances in the management of ACC will mainly depend on a better understanding of the molecular pathogenesis facilitating the use of modern cancer treatments (e.g. tyrosine kinase inhibitors). (J Clin Endocrinol Metab 91: 2027-2037, 2006)
Epidemiology
A DRENOCORTICAL TUMORS ARE common tumors with a prevalence of at least 3% in a population over the age of 50 yr (1, 2). In contrast, adrenocortical carcinoma (ACC) is a rare malignancy (incidence 1-2 per 1 million population) with a heterogeneous presentation and a vari- able but generally poor prognosis (3-5). However, data on incidence are mainly based on the National Cancer Institute survey from the early 1970s and probably underestimate the true incidence. An exceptionally high annual incidence of ACC has been reported for children in southern Brazil (3.4- 4.2 per 1 million children vs. an estimated worldwide inci- dence of 0.3 per 1 million children younger than 15 yr) and is related to a TP53 tumor suppressor gene mutation (6-8). Women are more often affected than men (ratio 1.5) (9-12). The age distribution is reported as bimodal with a first peak in childhood and a second higher peak in the fourth and fifth decade (4, 12).
First Published Online March 21, 2006
Abbreviations: ACC, Adrenocortical carcinoma; CNS, central ner- vous system; CT, computerized tomography; DHEA-S, dehydroepi- androsterone sulfate; FDG-PET, 18F-fluorodeoxyglucose positron emis- sion tomography; HU, Hounsfield unit; MRI, magnetic resonance imaging.
JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the en- docrine community.
Molecular Pathogenesis
The molecular pathogenesis of ACC has been the topic of recent reviews (13-16) but is still poorly understood. It is unclear whether ACCs evolve from adrenal adenomas after a second hit paradigm. Although such a sequence has been observed in occasional cases (17, 18), long-term follow-up data of incidentally discovered adrenal neoplasms suggest otherwise (19-21). Inactivating mutations at the 17p13 locus including the TP53 tumor suppressor gene and alterations of the 11p15 locus leading to IGF-II overexpression are fre- quently observed. In vitro experiments suggest that overex- pressed IGF-II acting via the IGF-I receptor is relevant for adrenal cancer cell proliferation (22-24). Thus, the IGF-II IGF-I receptor pathway is a promising target for future ther- apies in ACC (25).
Clinical Presentation
Patients present with evidence of adrenal steroid hormone excess in approximately 60% of cases. Rapidly progressing Cushing’s syndrome with or without virilization is the most frequent presentation. In patients from the German ACC Registry, autonomous cortisol secretion, either alone or in combination with other steroids, was detectable in 60% of the cases in which hormonal analysis had been performed prior to surgery (12). However, not in all of these cases was au- tonomous cortisol secretion clinically suspected. Androgen- secreting ACCs in women induce hirsutism and virilization
with deepening of the voice, male pattern baldness, and oligoamenorrhea. Estrogen-secreting adrenal tumors in males lead to gynecomastia and testicular atrophy and are almost invariably malignant (26). High concentration of de- hydroepiandrosterone sulfate (DHEA-S) is another clue sug- gesting ACC, whereas decreased serum DHEA-S concentra- tions are suggestive of a benign adenoma (26). Aldosterone- producing adrenocortical carcinomas present with hypertension and pronounced hypokalemia (mean serum potassium 2.3 ± 0.08 mmol/liter) (27). However, severe hypokalemia is more likely caused by grossly elevated cortisol secretion, leading to insufficient renal cortisol inactivation by 11ß-hydroxys- teroid dehydrogenase type 2 with consecutive activation of the mineralocorticoid receptor.
In many patients with a seemingly hormonally inactive ACC, high concentrations of steroid precursors like andro- stenedione or 17a-hydroxyprogesterone can often be dem- onstrated, thereby establishing the adrenocortical origin of the tumor.
Hormonally inactive ACCs usually present with abdom- inal discomfort (nausea, vomiting, abdominal fullness) or back pain caused by a mass effect of the large tumor. In the Italian survey on adrenal incidentaloma, the occurrence of pain was significantly associated with ACC and was not fully explained by large tumor size per se (28). However, an in- creasing percentage of ACCs is discovered as incidentaloma during abdominal imaging (28-31).
Only occasionally patients present with fever, weight loss, and anorexia, and it is a remarkable feature of non-cortisol- producing ACC that well-being is often little affected by even a large tumor burden.
Diagnosis
Hormonal work-up
Careful endocrine assessment is mandatory prior to sur- gery in ACC (Table 1). The pattern of hormone secretion may point to the malignant potential of the lesion (e.g. estradiol in males, high concentration of serum DHEA-S, or secretion of steroid precursors) and may thus affect surgical strategy (open instead of minimal invasive surgery). In addition, au-
tonomous cortisol secretion by the tumor is associated with the risk of postoperative adrenal insufficiency. Due to the variable hypercortisolemia and the rapid development of ACC, clinical features of Cushing’s syndrome are often in- complete or even missing (atypical or subclinical Cushing’s syndrome). To establish tumor markers for monitoring of tumor recurrence, a thorough hormonal work-up is essential. Finally, it is important to exclude a pheochromocytoma prior to surgery because imaging often cannot reliably differenti- ate between ACC and pheochromocytoma (26).
Imaging
Both size and appearance of an adrenal mass on comput- erized tomography (CT), magnetic resonance imaging (MRI), and more recently 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) have been used to distinguish be- tween benign and malignant lesions. The size of the adrenal mass, as measured by CT or MRI remains one of the best indicators of malignancy. In the German Adrenal Cancer Registry (n = 215), the mean tumor size at diagnosis was 11.5 ± 4.7 cm (range 3-28 cm). However, ACCs smaller than 6 cm have been increasingly reported (5), and it is intuitively obvious that during early development ACCs are small, and surgical intervention would be most beneficial at this stage. According to the National Institutes of Health consensus conference, tumors larger than 6 cm are highly suspicious for malignancy and will be removed (1, 2). Therefore, tumors between 3 and 6 cm represent the main diagnostic challenge. To avoid misclassification of a small ACC as benign neopla- sia, follow-up imaging is mandatory to detect early tumor growth and should be performed initially every 3-12 months (depending on tumor size and radiological appearance).
Thin-collimation CT. ACCs are inhomogeneous with irregular margins and irregular enhancement of solid components after iv contrast media. Sometimes calcifications are visible. Local invasion or tumor extension into the inferior vena cava as well as lymph node or other metastases (lung and liver) are often found in advanced ACC (Fig. 1). Measurement of Hounsfield units (HU) in unenhanced CT is of great value in
| Hormonal work-up Glucocorticoid excess (minimum 3 of 4 tests) | Dexamethasone suppression test (1 mg, 2300 h) Excretion of free urinary cortisol (24 h urine) |
| Basal cortisol (serum) Basal ACTH (plasma) | |
| Sexual steroids and steroid precursors | DHEA-S (serum) 17-OH-progesterone (serum) |
| Androstendione (serum) | |
| Testosterone (serum) | |
| 17ß-estradiol (serum, only in men and postmenopausal women) | |
| Mineralocorticoid excess | Potassium (serum) Aldosterone to renin ratio (only in patients with arterial hypertension and/or hypokalemia) |
| Exclusion of a pheochromocytoma (1 of 2 tests) | Catecholamine excretion (24 h urine) Meta- and normetanephrines (plasma) |
| Imaging | CT or MRI of abdomen and thorax Bone scintigraphy (when suspecting skeletal metastases) FDG-PET (optional) |
differentiating malignant from benign adrenal lesions. Using a threshold value of 10 HU sensitivity and specificity for characterization an adrenal lesion as a benign adenoma in unenhanced CT was 71 and 98%, respectively, in a meta- analysis of 10 studies (32). However, in a recent series from Cleveland including 151 adrenal masses with histologically confirmed diagnosis, the median unenhanced HU was 19 (range: - 19 to 43) for adenomas and 36 (31-43) for carci- nomas, indicating overlap between both groups (33). For better discrimination of lipid-poor adenomas from ACC, a delayed contrast-enhanced CT can be used, analyzing wash- out of contrast medium. Adrenal lesions with an attenuation value of more than 10 HU in unenhanced CT or an enhance- ment washout of less than 50% and a delayed attenuation of more than 35 HU (on 10- to 15-min delayed enhanced CT) are suspicious for malignancy (34-40).
Modern MRI with dynamic gadolinium enhanced- and chemical shift technique is equally effective as CT in distin- guishing malignant from benign lesions (1,31, 41). Again, the fat content contributes to the differentiation between benign and malignant adrenal tumors (42). ACCs present typically isointense to liver on T1-weighted images and show inter- mediate to increased intensity at T2-weighted sequences. Enhancement after gadolinium is distinct and washout is usually slow. Based on these features, the sensitivity of MRI for differentiation of benign and malignant adrenal masses ranged between 81 and 89% with a specificity between 92 and 99% (43-46). The optimum MRI method (T1/T2 relaxation time, chemical shift, fast low angle shot, etc.) for diagnosis of ACC remains a matter of controversy (31, 47). MRI is also useful in planning surgery because invasion into adjacent organs and the inferior vena cava is best determined with this
method. However, MRI is more expensive and less stan- dardized than CT. At present, each center should use these methods according to the experience of the local radiologist. Images of a suspected ACC should also be reviewed by the attending endocrinologist.
Adrenal scintigraphy with iodocholesterol analogs is not widely available, is time consuming (3-5 d), and is associated with relatively high dosage of radiation; and the diagnostic value beyond CT and MRI is controversial (2, 26, 31). In contrast, recent studies have demonstrated good perfor- mance of FDG-PET in differentiating malignant from benign adrenal lesions in patients with proven or suspected malig- nancy (48-53). Due to the limited number of ACC cases, more studies are needed to validate further the role of FDG- PET and also in detecting metastases during follow-up.
A new method for adrenal imaging is 11C-metomidate- PET. Metomidate binds to adrenal 11ß-hydroxylase and is therefore an excellent tool to distinguish lesions of adreno- cortical origin from other lesions (54-58). It may be partic- ularly helpful to characterize potential metastatic disease in ACC.
Imaging is important not only for characterizing adrenal lesions but also for staging. High-resolution CT of chest and abdomen (alternatively MRI) is mandatory because lung and liver are most frequently affected by metastases. At the time of diagnosis and in case of bone pain, a bone scintigraphy followed by conventional x-ray studies of regions with an increased uptake is performed. In case of presumed complete surgical resection, hormone measurements should confirm the absence of residual tumor.
In contrast to other tumor entities, biopsy of adrenal tu- mors has been controversial in the past and has never gained general acceptance because of needle tract metastases and limited diagnostic value in differentiating benign from ma- lignant lesions (26, 59). In suspected ACC, a biopsy should be performed only if a surgical approach is not feasible and the diagnosis cannot be established otherwise before starting medical therapy.
Pathological Assessment
Pathological diagnosis should be performed by an expe- rienced pathologist. Differentiation between benign and ma- lignant adrenal lesions is based on macroscopic features (tu- mor weight, hemorrhage, breached or intact tumor capsule) and a microscopic diagnostic score with the Weiss score, the most widely used tool (60). Nuclear atypia, atypical and frequent mitoses (more than five of 50 high-power fields), vascular and capsular invasion, and necroses are suggestive of malignancy. In addition, broad fibrous bands are a char- acteristic feature separating ACC from benign tumors. Care- ful assessment of the R-status is of great importance but unfortunately still often missing in the pathology report.
Important additional information is gained from immu- nohistochemistry. Several studies have demonstrated the value of Ki67 staining in differentiating benign from malig- nant lesions (61-64). In addition, Ki67 expression may be of prognostic relevance as high expression (>10%) has been associated with poor survival (unpublished results from the German ACC Registry). Other markers like D11, inhibin-a,
melan A, and chromogranin A are helpful to define or ex- clude the adrenocortical origin of the tumor (65, 66). Finally, several new markers (LOH at 17p13, IGF-II overexpression, cyclin E) have been proposed to separate benign from ma- lignant adrenal lesions (67).
Staging
Until 2004, no official tumor nodes and metastasis (TNM) classification was available for ACC, and different staging systems were used (68-72), most often the Sullivan modifi- cation of the Macfarlane system. Accordingly, the new Union International Contre Cancer (UICC) staging system pub- lished by the World Health Organization (WHO) in 2004 is based on this classification (73). Stages I and II describe localized tumors 5 cm or smaller and larger than 5 cm, re- spectively. Locally invasive tumors or tumors with regional lymph node metastases are classified as stage III, whereas stage IV consists of tumors invading adjacent organs or pre- senting with distant metastases. However, the prognostic value of the different staging systems has never been com- pared directly in a large series of patients. Because one of the major objectives of staging classifications is to facilitate the exchange of information between treatment centers, we cur- rently recommend the use of the new WHO system until evidence that a modification is needed becomes available.
Whereas in older series (10, 68, 74, 75) most patients were diagnosed with advanced disease (stage IV), recent studies have reported the highest percentage of patients in stage II (11,76-78), most likely reflecting improved and more widely available imaging technology.
Therapy (Fig. 2)
Surgery
In stages I-III complete tumor removal by a specialized surgeon offers by far the best chance for cure (5, 71, 72, 77, 79-81). In particular, an RO resection is associated with a superior prognosis. Surgery often needs to be extensive with en bloc resection of invaded organs and regularly includes lymphadenectomy. It is of utmost importance to leave the tumor capsule intact, thereby avoiding tumor spillage and reducing risk for local recurrence (5). The presence of a tumor thrombus in the inferior vena cava or the renal vein is com- patible with complete tumor resection but occasionally ne- cessitates cardiac bypass technique (5, 79, 81).
A matter of debate is the use of laparoscopic adrenalec- tomy for ACC. Since its introduction in 1992, minimal inva- sive adrenalectomy has become the treatment of choice for benign adrenal lesions with a diameter of less than 6 cm (2, 82) because of less postoperative pain and a shorter hospital stay (83). At present, there is a consensus that open adre- nalectomy remains the operation of choice for ACC with invasion of adjacent organs, enlarged regional lymph nodes, or tumors larger than 10-12 cm in size (59, 84, 85). Cobb et al. (86) reviewed the literature and identified 25 cases of ACC removed by laparoscopic resection. Local recurrence or ip dissemination occurred in 40% of patients. High local recur- rence after laparoscopic adrenalectomy was also observed in a recent series reported by Gonzalez et al. (78). Therefore, laparoscopic adrenalectomy for ACC should be performed only in patients included in adequately designed prospective trials. Patients undergoing laparoscopic adrenalectomy for
Stage I-III
Stage IV
complete surgical resection
consider surgery (incl. metastases)
successful
not successful
complete resectiond
not possible or incomplete resection
consider adjuvant therapy a:
- mitotaneb (+/- streptozotocin) and / or - tumor bed radiation
mitotane only b or combined with streptozotocin or EDP (FIRM-ACT study)
follow-up every 2 months
follow-up every 3 months c imaging and tumor markers
tumor regression / stable disease
progressive disease
tumor free
recurrence
consider surgery + continue therapy
add / switch chemotherapy e
suspected ACC should be informed that at present this op- eration is not regarded as the standard of care.
The role of tumor debulking in the presence of metastatic disease is a matter of debate. Incomplete resection of the primary tumor or metastatic disease not amenable to surgery is associated with a particularly poor prognosis. In most studies the median survival is less than 12 months (72, 80, 87, 88). However, tumor debulking may help to control hormone excess and may in individual cases facilitate other therapeu- tic options.
Surgery for local recurrences or metastatic disease is ac- cepted as a valuable therapeutic option and was associated with improved survival in retrospective studies (59, 76, 89, 90).
Radiofrequency thermal ablation
This has shown promise as a technique for treating solid tumors involving the liver, kidney, and lung in selected patients. There is evidence that this method may be an al- ternative to surgery in some patients with metastatic ACC and lesions less than 5 cm in size (91), but its utility and value remain to be proven, and potential benefits have to be weighed against complications (59, 92, 93).
Radiation therapy
Radiotherapy has been often considered ineffective for treatment of ACC (9, 74, 94, 95). However, several reports have described tumor response rates up to 42% (75, 96-103). Although methods and response criteria in these studies did not fulfill modern standards and although the number of patients was small, these reports indicate that ACC is not resistant to radiation therapy. Therefore, we recommend considering radiation therapy to control localized disease not amenable to surgery. For most bone (and brain) metastases, radiation therapy is the treatment of choice (30-40 Gy) (59). For optimum results, an experienced radiotherapist using modern treatment concepts with CT planning, high-voltage radiation, and multiple fields is required.
Even less information is available concerning adjuvant radiotherapy after surgery. Stewart et al. (104) were the first to use radiation therapy in an adjuvant setting after (pre- sumably complete) surgery. Of note, in a series of children with ACC, metastatic disease was invariably preceded by local recurrence of the disease (105). Based on these obser- vations and further small studies (97, 99, 102), we recently offered patients with stage III ACC or high-risk stage II postoperative radiotherapy of the tumor bed (45-55 Gy over 4-5 wk). A first analysis demonstrated reduced local recur- rence, compared with matched controls (106). A randomized trial seems to be justified to evaluate the efficacy of this treatment option.
Medical therapy
Mitotane (Tables 2-4). Mitotane (o,p’-DDD) is the only adrenal- specific agent available for treatment of ACC. Mitotane ex- erts a specific cytotoxic effect on adrenocortical cells pro- ducing focal degeneration of the fascicular and particularly the reticular zone, whereas changes of the zona glomerulosa are relatively slight. Metabolic activation is essential for its
adrenolytic activity. The reactive acyl-chloride either co- valently binds to macromolecules, predominantly mitochon- drial proteins and thereby mediates the biological activity of mitotane, or is transformed to the acetic acid derivative o,p’- dichlorodiphenyl acetic acid, the main metabolite of mito- tane (107). In addition, oxidative damage through produc- tion of free radicals may contribute to the adrenolytic effect of mitotane (108). Impairment of adrenal steroidogenesis is also due to a direct inhibitory effect on steroidogenic en- zymes (107).
Mitotane is given as tablets [Lysodren; HRA Pharma (Paris, France), Bristol Meyer Squibb (New York, NY)] ac- cording to tolerability and blood levels (see text below). Despite the long history of mitotane use in ACC and its approval by the Food and Drug Administration in 1970, it is not available in all countries. Only in 2004 was it approved by the European Medicine Agency. In the first study by Bergenstal et al. (109, 110), seven of 18 patients with ACC showed significant tumor regression. Even more favorable was the report by Lubitz et al. (111) describing tumor re- gression in 46 of 75 patients (61%) with measurable disease. However, publications thereafter showed a lower response rate. We recently analyzed the efficacy of mitotane treatment in advanced ACC including only prospective studies or re- ports with more than 10 patients from the last 20 yr (107). Based on this analysis, it was concluded that mitotane leads to an objective tumor regression in about 25% of cases (Table 2) and control of hormone excess in the majority of patients. Although a complete response (or even cure) in patients with advanced ACC is extremely rare, long-term survival has been reported (112-119).
Several publications have established the impact of mon- itoring blood mitotane concentrations for predicting efficacy and toxicity. Although a threshold mitotane concentration of 14 mg/liter for antitumor response was defined retrospec- tively (120), this threshold has been confirmed in further studies (121-123) because objective tumor responses were found only among patients with mitotane concentrations greater than 14 mg/liter. Interestingly, Baudin et al. (122) reported that the four patients who initially responded to mitotane therapy had mitotane levels less than 14 mg/liter at the time of disease progression. However, Seki et al. (124) presented a case with complete remission of local recurrence and lung metastases with mitotane plasma levels never above 10 mg/liter. The daily dosage needed to achieve and maintain blood levels greater than 14 mg/liter is variable. Two studies (122, 125) suggested that mitotane blood levels in humans correlate better with the cumulative dose than with daily dosage. Nevertheless, in some patients adminis- tration of 2 g daily is sufficient to bring blood levels into the target range, whereas in others 5 g/d fails to reach target levels. In most patients we initiate treatment with 1.5 g/d and rapidly increase the dose, depending on gastrointestinal tol- erance, to 5-6 g/d. This high-dose regimen requires mea- surement of mitotane blood levels 14 d after initiation of therapy. Afterward, the dose is adjusted according to mito- tane plasma concentrations and tolerability.
Mitotane has a narrow therapeutic window, and adverse effects occur frequently and are often dose limiting. More than 80% of all patients experience at least one undesirable
| Center | n | Response | Comments | Ref. | ||
|---|---|---|---|---|---|---|
| CR (n) | PR (n) | Total (%) | ||||
| Houston, TX | 72 | 21 | 29 | 101 | ||
| Paris, France | 37 | 8 | 22 | PR was defined as regression of the area of at least one measurable tumor deposit by more than 10% | 9 | |
| Multicenter, United Statesb | 36 | 2 | 6 | 22 | Median survival: 50 months in responders vs. 15 months in nonresponders | 154 |
| Leiden, The Netherlands | 55 | 8 | 7 | 27 | Median survival: 29 months in patients with mito- tane > 14 mg/liter and 13 months in patients with mitotane < 14 mg/liter. Responses were seen only in patients with mitotane > 14 mg/liter. | 121 |
| Padua, Italy | 11 | 2 | 18 | Patients were included only after failure with cisplatin+etoposide | 155 | |
| Multicenter, United Statesb | 16 | 2 | 13 | 156 | ||
| Heidelberg, Germanyb | 6 | 3 | 50 | Median survival: 34 months in patients with mito- tane > 14 mg/liter and 5 months in patients with mitotane < 14 mg/liter. Responses were seen only in patients with mitotane > 14 mg/liter. | 123 | |
| Multicenter, France | NR | NR | Median survival: 39 wk in patients treated with mi- totane (n = 40) vs. 11 wk in patients without mi- totane (n = 20) | 11 | ||
| Villejuif, Franceb | 13 | 1 | 3 | 31 | Responses were seen only in patients with mitotane > 14 mg/liter. | 122 |
| Sum | 246 | 11 | 52 | 26 | ||
CR, Complete response; PR, partial response.
” Only reports with more than 10 patients or prospectively performed studies were included. Response criteria are described in detail elsewhere (107).
b Prospective study.
effect (Table 4). These effects are mainly gastrointestinal or involve the central nervous system (CNS) (111, 126, 127). The probability of CNS adverse effects increases strongly with mitotane blood level greater than 20 mg/liter. In general, adverse effects are reversible after cessation of mitotane (128, 129). Due to the long half-life of mitotane, blood levels and adverse effects usually increase over time, even if the dose remains unchanged. For management of nausea, 5-hydroxy- tryptamine blockers may be useful. In case of significant neuropsychiatric side effects, drug treatment is interrupted for a minimum of 1 wk and restarted with a lower dose.
Due to its adrenolytic activity, mitotane treatment induces
adrenal insufficiency. Because mitotane also increases the metabolic clearance of glucocorticoids (130), high-dose glu- cocorticoid replacement (e.g. 50 mg hydrocortisone daily) is needed. Inadequate glucocorticoid substitution enhances mi- totane-induced adverse effects and reduces mitotane tolerance.
The high recurrence rate of up to 85% in ACC (103, 131, 132) prompted investigators to use mitotane in an adjuvant setting. First evidence for a benefit of this approach derived from two retrospective reports describing 10 patients who received mitotane after complete surgery with a survival clearly above historical controls (101, 127). More recently
| Center | Mitotane | Control | Comments | Ref. | ||||
|---|---|---|---|---|---|---|---|---|
| n | DFS (months) | Survival (months) | n | DFS (months) | Survival (months) | |||
| New York, NY | 7 | 29 | NR | 43 | 30 | NR | DFS is given as mean. The mitotane group included three pa- tients treated with adjuvant radiotherapy. | 103 |
| Houston, TX | 8 | 10 | 14 | 6 | 23 | 34 | Difference in DFS is significant (P < 0.01) | 135 |
| Leiden, The Netherlands | 11 | NR | 51 | 15 | NR | 61 | Six of 11 patients in the mitotane group reached mitotane levels > 14 mg/liter | 121 |
| Padua, Italy | 7 | 8 | 24 | 11 | 13 | 54 | Difference not significant Five of seven patients in mitotane group are disease free at time of last follow-up (range 5-54 months), in contrast to three of 11 in control group | 155 |
| Haifa, Israel | 6 | >46 | >46 | Five of six patients were still disease free at the time of last follow-up | 133, 134 | |||
| Villejuif, Franceb | 11 | 7 | 24 | Three of 11 patients were still disease free Six of eight patients with recurrence had mitotane levels > 14 mg/liter | 122 | |||
DFS (disease-free survival) and survival are described as median if not stated otherwise. NR, Not reported.
” Only reports with detailed description of DFS were included.
b Prospective study.
| Adverse effect | Frequency |
|---|---|
| Gastrointestinal: nausea, vomiting, diarrhea, anorexia, mucositis CNS: lethargy, somnolence, vertigo, ataxia confusion, depression, dizziness, decreased memory, polyneuropathy | Very common |
| Very common, common | |
| Adrenal insufficiency | Very common |
| Primary hypogonadism in men | Common |
| Gynecomastia | Common |
| Skin rash | Common |
| Autoimmune hepatitis | Rare |
| Cardiovascular: hypertension | Very rare |
| Ocular: blurred vision, double vision, toxic retinopathy, cataract, macular edema | Very rare |
| Hemorrhagic cystitis | Very rare |
| Increase of hepatic enzymes (in particular y-GT) | Very common |
| Increase in hormone binding globulins (CBG, SHBG, TBG, vitamin D binding protein) | Very common |
| Disturbance of thyroid parameters (interference with binding of T4 to TBG, total T4 V ) | Very common |
| Hypercholesterolemia, hypertriglyceridemia Prolonged bleeding time | Very common |
| Leucopenia | Common |
| Thrombocytopenia, anemia | Rare |
| Hematuria, albuminuria | Very rare |
| Hepatic microsomal enzyme induction with increased metabolism of glucocorticoids and other steroids and barbiturates, phenytoin, warfarin | Very common, common |
GT, Glutamyl transpeptidase; CBG, cortisol-binding globulin; TBG, thyroxin-binding globulin.
” Modified by the authors based on information published by the European Medicine Agency (EMEA; http://www.emea.eu.int).
Dickstein and colleagues (133, 134) described six patients treated with mitotane after complete surgery, of which five were disease free after a median follow-up of 46 months. However, the majority of studies could not find a benefit of adjuvant mitotane (Table 3). One study even reported a det- rimental effect. In this study mitotane was offered to all patients after complete surgery between (n = 14) (135). Un- expectedly, the six patients who refused mitotane had a favorable disease-free and overall survival in comparison with the eight patients treated with mitotane. However, the two groups in this nonrandomized study were probably not comparable (e.g. median tumor size 6 cm vs. 10 cm, n.s.). Thus, a randomized, controlled trial is urgently needed to finally evaluate the efficacy of mitotane as adjuvant treat- ment option in ACC.
Cytotoxic chemotherapy. Experience with cytotoxic chemother- apy in ACC is still limited (for review see Refs. 119 and 136). Several combinations of cytotoxic agents have been used, and the available evidence suggests that cisplatin alone or in combination with etoposide has some activity in ACC. How- ever, only a minority of patients respond to current protocols, with the exception of a treatment regimen from Italy com- bining mitotane with etoposide, doxorubicin, and cisplatin. According to WHO criteria, the overall response rate in 72 patients was 49%, including five patients with complete re- sponse (137). This success comes at the cost of significant toxicity. As a less toxic protocol, a combination of mitotane and streptozotocin has been proposed (138). Complete or partial responses were observed in 36% of patients with measurable disease. Of note, Khan et al. (139) recently re- ported a second-line cytotoxic chemotherapy regimen in 11 patients after failure of streptozotocin plus mitotane. Using a combination of vincristine, cisplatin, teniposide, and cy- clophosphamide, they observed a partial response in two patients and stable disease in seven patients with a median survival of 21 months after the start of second-line chemo-
therapy. This is the first study on a second-line chemother- apy in ACC including more than 10 patients demonstrating activity in a significant number of patients.
The success of both the Berruti protocol and the combi- nation of streptozotocin and mitotane has led to the first ever phase III trial in ACC directly comparing these treatment options [First International Randomized Trial in Locally Ad- vanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT), see below].
The limited response to cytotoxic therapy in ACC has been linked to high expression of the multidrug-resistant gene mdr-1, resulting in high concentrations of p-glycoprotein acting as a drug efflux pump (140). Antagonists of p-glyco- protein may therefore enhance the efficacy of cytotoxic ther- apy, and in vitro evidence that mitotane may reverse mul- tidrug resistance has been the rationale to combine cytotoxic treatment with mitotane (141, 142). However, it remains un- certain to what extent mitotane also enhances tumor respon- sivity to cytotoxic drugs in vivo (140).
Treatment of hormone excess. Hypersecretion of hormonal ste- roids in ACC frequently contributes to the disease burden and can severely affect quality of life. In particular, Cushing’s syndrome often induces hypokalemia, muscle wasting, os- teoporotic fractures, and infectious complications. Due its slow onset of action and its dose-limiting toxicity, mitotane treatment alone is frequently insufficient to rapidly control hypersecretion in all patients. Adrenostatic drugs like keto- conazole, metyrapone, aminoglutethimide, and etomidate have been successfully used to block steroidogenic enzymes and to lower circulating cortisol into the normal range (143, 144). Some of the drugs also possess antiproliferative activity in vitro (145), and even occasional tumor responses have been reported (146). Ketoconazole (400-1200 mg/d) is most often used and can be combined with mitotane. Intravenous eto- midate (e.g. 80 mg/d as continuous infusion) potently lowers circulating cortisol levels and can be used in emergencies (e.g.
glucocorticoid-induced psychosis) (147, 148). With all ad- renostatic drugs, close monitoring by an experienced endo- crinologist is mandatory to keep cortisol in the target range and to avoid adrenal insufficiency.
Based on a case report, the use of spironolactone to correct hypokalemia may impair the antitumor activity of mitotane (149). Although the exact mechanism is not known, we prefer the use of amiloride in hypokalemic patients on mitotane.
Follow-Up and Prognosis
In functioning tumors, hormonal markers should be mea- sured every 3 months for early detection of tumor recurrence. However, in most patients imaging is more sensitive for monitoring tumor recurrence. Because surgical removal of a local relapse or metastases is a valid therapeutic option, restaging every 3 months by CT (abdomen plus chest) during the first 2 yr is mandatory. However, even after 2 yr, patients remain at high risk for relapse. Thus, whereas imaging in- tervals may increase, regular restaging should go on for at least 5 yr.
The role of FDG-PET in follow-up remains to be defined. First studies suggest that PET may be particularly helpful for detecting local recurrence. However, small pulmonary me- tastases (diameter < 1 cm) are often not visualized (150).
Prognosis depends largely on tumor stage. In a series from France including 253 patients, the 5-yr survival rates were 60% for stage I, 58% for stage II, 24% for stage III, and 0% for stage IV. The overall 5-yr survival in different series ranged between 16 and 38% (9, 11, 80, 95, 101, 103, 121, 151, 152). Median survival for metastatic disease (stage IV) at the time of diagnosis is still consistently less than 12 months.
There are limited data to define additional prognostic markers for survival beyond stage. Functionality, age, or sex seem to play no major role (9, 98, 101, 132, 152). Large tumor size (diameter > 12 cm) has been associated with inferior survival after complete resection (132, 153). In addition, a high mitotic rate, tumor necroses, atypic mitotic figures, high Ki67 staining, and evidence of mutated TP53 have been as- sociated with advanced ACC and poor prognosis (132). However, these findings need confirmation in further studies.
Prognostic markers are of particular interest in patients after RO resection to better define populations, which may or may not benefit from adjuvant treatment strategies.
Structural Progress and Future Perspectives
Since our last review (119), remarkable changes have set the stage for continuous progress in the therapy of ACC. After a consensus meeting initiated by the Ann Arbor group (59), the first ever phase III trial in ACC was designed and is currently open for recruitment (FIRM-ACT trial, www. firm-act.org). In this multinational prospective trial, patients with advanced ACC are randomized to either a slightly mod- ified Berruti protocol [mitotane plus doxorubicin (40 mg/m2 on d 1), etoposide (100 mg/m2 on d 2-4), and cisplatin (40 mg/m2 on d 3-4) (137)] or the Khan protocol [mitotane plus streptozotocin (1 g/d for 5 d, thereafter 2 g once every 3 wk) (138)]. Patients with progressive disease during cytotoxic chemotherapy are offered the alternative protocol. At the
time of this writing, the trial has already included 69 patients in less than 22 months, making it the second largest study to date. Although recruitment rate compares favorably with previous studies and is still increasing, it will take several years to include the intended 300 patients into this study. The FIRM-ACT trial will not only generate a benchmark cytotoxic chemotherapy against which future treatments will be com- pared but also create a structural basis for further research in ACC. To this end, concepts are presently being developed in the participating centers to evaluate adjuvant treatment pro- tocols after seemingly curative surgery.
In addition, central registries in several countries (e.g. Italy, France, and Germany) for patients with ACC have been initiated. These registries not only collect important data from large series of patients with ACC, but they will also improve patient care on a national level and will facilitate recruitment for further trials. In Europe, the European Net- work for the Study of Adrenal Tumors has been founded, interconnecting these national initiatives. It will provide a common database supported by a standardized tumor-bank- ing protocol allowing for the exchange of data and high- quality tumor material.
These recent developments indicate that after decades of limited progress, systematic advances can now take place.
There is little doubt that current treatment protocols are often disappointing and that better therapies are needed. The increasing availability of therapeutic monoclonal antibodies and tyrosine kinase inhibitors also holds great potential for improved outcomes in patients with ACC. These perspec- tives have led to new concepts and phase II trials in the United States recently reviewed in this journal (25). How- ever, true progress will only follow a better understanding of the molecular pathogenesis of ACC. Variable clinical pre- sentation and wide differences in biological behavior indi- cate significant heterogeneity of ACC. Thus, predicting tu- mor response to drugs (e.g. mitotane) will greatly influence quality of life and prognosis of patients with ACC. Again, the FIRM-ACT trial with hundreds of prospectively documented patients and its structured collection of tumor material will help to bring together molecular and clinical data.
Acknowledgments
Received December 7, 2005. Accepted March 9, 2006.
Address all correspondence and requests for reprints to: Bruno Allo- lio, M.D., Endocrinology and Diabetes Unit, Department of Medicine I, University Hospital Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuer- zburg, Germany. E-mail: allolio_b@medizin.uni-wuerzburg.de; or fassnacht_m@medizin.uni-wuerzburg.de.
This work was supported by Deutsche Krebshilfe Grant 106080 (to B.A.) and European Union Grant MOIF-7394 (to M.F.).
The authors declare that there is no conflict of interest.
References
1. National Institutes of Health 2002 NIH state-of-the-science statement on management of the clinically inapparent adrenal mass (“incidentaloma”). NIH Consens State Sci Statements 19:1-25
2. Grumbach MM, Biller BM, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JK, Oertel YC, Posner MC, Schlechte JA, Wieand HS 2003 Management of the clinically inapparent adrenal mass (“inciden- taloma”). Ann Intern Med 138:424-429
3. National Cancer Institute 1975 Third national cancer survey: incidental data. DHEW publication no. (NIH) 75-787. NCI Monogr 41
4. Wajchenberg B, Albergaria PM, Medonca B, Latronico A, Campos CP, Ferreira AV, Zerbini M, Liberman B, Carlos GG, Kirschner M 2000 Adre- nocortical carcinoma: clinical and laboratory observations. Cancer 88:711-736
5. Dackiw AP, Lee JE, Gagel RF, Evans DB 2001 Adrenal cortical carcinoma. World J Surg 25:914-926
6. Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis CA, Sandrini R 2001 An inherited p53 mutation that contributes in a tissue- specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330-9335
7. Michalkiewicz E, Sandrini R, Figueiredo B, Miranda EC, Caran E, Oliveira- Filho AG, Marques R, Pianovski MA, Lacerda L, Cristofani LM, Jenkins J, Rodriguez-Galindo C, Ribeiro RC 2004 Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pe- diatric Adrenocortical Tumor Registry. J Clin Oncol 22:838-845
8. Pianovski MA, Maluf EM, de Carvalho DS, Ribeiro RC, Rodriguez-Gal- indo C, Boffetta P, Zancanella P, Figueiredo BC 30 September 2005 Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer 10.1002/pbc.20624
9. Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y, Blondeau P, Bonnin A, Bricaire H 1990 Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med 322:1195-1201
10. Wooten MD, King DK 1993 Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72:3145-3155
11. Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF, Proye C 2001 Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons Study Group. World J Surg 25:891-897
12. Koschker AK, Fassnacht M, Hahner S, Weismann D, Allolio B 2006 Ad- renocortical carcinoma: improving patient care by establishing new struc- tures. Exp Clin Endocrinol Diabetes 114:45-51
13. Kirschner LS 2002 Signaling pathways in adrenocortical cancer. Ann NY Acad Sci 968:222-239
14. Koch CA, Pacak K, Chrousos GP 2002 The molecular pathogenesis of he- reditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 87:5367-5384
15. Sidhu S, Sywak M, Robinson B, Delbridge L 2004 Adrenocortical cancer: recent clinical and molecular advances. Curr Opin Oncol 16:13-18
16. Libe R, Bertherat J 2005 Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 153:477-487
17. Bernard MH, Sidhu S, Berger N, Peix JL, Marsh DJ, Robinson BG, Gaston V, Le Bouc Y, Gicquel C 2003 A case report in favor of a multistep adre- nocortical tumorigenesis. J Clin Endocrinol Metab 88:998-1001
18. Cofield 3rd KR, Cantley LK, Geisinger KR, Zagoria RJ, Perrier ND 2005 Adrenocortical carcinoma arising from a long-standing adrenal mass. Mayo Clin Proc 80:264-266
19. Barzon L, Scaroni C, Sonino N, Fallo F, Paoletta A, Boscaro M 1999 Risk factors and long-term follow-up of adrenal incidentalomas. J Clin Endocrinol Metab 84:520-526
20. Barzon L, Sonino N, Fallo F, Palu G, Boscaro M 2003 Prevalence and natural history of adrenal incidentalomas. Eur J Endocrinol 149:273-285
21. Bernini GP, Moretti A, Oriandini C, Bardini M, Taurino C, Salvetti A 2005 Long-term morphological and hormonal follow-up in a single unit on 115 patients with adrenal incidentalomas. Br J Cancer 92:1104-1109
22. Logie A, Boulle N, Gaston V, Perin L, Boudou P, Le Bouc Y, Gicquel C 1999 Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. J Mol Endocrinol 23:23-32
23. Reincke M, Fassnacht M, Vath S, Mora P, Allolio B 1996 Adrenal inciden- talomas: a manifestation of the metabolic syndrome? Endocr Res 22:757-761
24. Fottner C, Hoeflich A, Wolf E, Weber MM 2004 Role of the insulin-like growth factor system in adrenocortical growth control and carcinogenesis. Horm Metab Res 36:397-405
25. Kirschner LS 2005 Emerging treatment strategies for adrenocortical carci- noma: a new hope. J Clin Endocrinol Metab 91:14-21
26. Fassnacht M, Kenn W, Allolio B 2004 Adrenal tumors: how to establish malignancy? J Endocrinol Invest 27:387-399
27. Seccia TM, Fassina A, Nussdorfer GG, Pessina AC, Rossi GP 2005 Aldo- sterone-producing adrenocortical carcinoma: an unusual cause of Conn’s syndrome with an ominous clinical course. Endocr Relat Cancer 12:149-159
28. Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A, Giovagnetti M, Opocher G, Angeli A 2000 A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 85:637-644
29. Kasperlik-Zeluska AA, Roslonowska E, Slowinska-Srzednicka J, Migdal- ska B, Jeske W, Makowska A, Snochowska H 1997 Incidentally discovered adrenal mass (incidentaloma): investigation and management of 208 patients. Clin Endocrinol (Oxf) 46:29-37
30. Barzon L, Boscaro M 2000 Diagnosis and management of adrenal inciden- talomas. J Urol 163:398-407
31. Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR 2004 The
clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 25:309-340
32. Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR 1998 Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am J Roentgenol 171:201-204
33. Hamrahian AH, Ioachimescu AG, Remer EM, Motta-Ramirez G, Boga- bathina H, Levin HS, Reddy S, Gill IS, Siperstein A, Bravo EL 2005 Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol Metab 90:871-877
34. Lee M, Hahn P, Papanicolaou N, Egglin T, Saini S, Mueller P, Simeone J 1991 Benign and malignant adrenal masses: CT distinction with attenuation coefficients, size, and observer analysis. Radiology 179:415-418
35. Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Londy F 1998 CT time-attenuation washout curves of adrenal adenomas and nonadenomas. AJR Am J Roentgenol 170:747-752
36. Szolar DH, Kammerhuber FH 1998 Adrenal adenomas and nonadenomas: assessment of washout at delayed contrast-enhanced CT. Radiology 207:369- 375
37. Caoili EM, Korobkin M, Francis IR, Cohan RH, Dunnick NR 2000 Delayed enhanced CT of lipid-poor adrenal adenomas. AJR Am J Roentgenol 175: 1411-1415
38. Pena CS, Boland GW, Hahn PF, Lee MJ, Mueller PR 2000 Characterization of indeterminate (lipid-poor) adrenal masses: use of washout characteristics at contrast-enhanced CT. Radiology 217:798-802
39. Caoili EM, Korobkin M, Francis IR, Cohan RH, Platt JF, Dunnick NR, Raghupathi KI 2002 Adrenal masses: characterization with combined un- enhanced and delayed enhanced CT. Radiology 222:629-633
40. Szolar DH, Korobkin M, Reittner P, Berghold A, Bauernhofer T, Trummer H, Schoellnast H, Preidler KW, Samonigg H 2005 Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrast-enhanced CT. Radiology 234:479-485
41. Outwater EK, Siegelman ES, Huang AB, Birnbaum BA 1996 Adrenal mass- es: correlation between CT attenuation value and chemical shift ratio at MR imaging with in-phase and opposed-phase sequences. Radiology 200:749-752
42. Korobkin M, Giordano TJ, Brodeur FJ, Francis IR, Siegelman ES, Quint LE, Dunnick NR, Heiken JP, Wang HH 1996 Adrenal adenomas: relationship between histologic lipid and CT and MR findings. Radiology 200:743-747
43. Bilbey JH, McLoughlin RF, Kurkjian PS, Wilkins GE, Chan NH, Schmidt N, Singer J 1995 MR imaging of adrenal masses: value of chemical-shift imaging for distinguishing adenomas from other tumors. AJR Am J Roent- genol 164:637-642
44. Korobkin M, Lombardi TJ, Aisen AM, Francis IR, Quint LE, Dunnick NR, Londy F, Shapiro B, Gross MD, Thompson NW 1995 Characterization of adrenal masses with chemical shift and gadolinium-enhanced MR imaging. Radiology 197:411-418
45. Heinz-Peer G, Honigschnabl S, Schneider B, Niederle B, Kaserer K, Lech- ner G 1999 Characterization of adrenal masses using MR imaging with histopathologic correlation. AJR Am J Roentgenol 173:15-22
46. Honigschnabl S, Gallo S, Niederle B, Prager G, Kaserer K, Lechner G, Heinz-Peer G 2002 How accurate is MR imaging in characterisation of ad- renal masses: update of a long-term study. Eur J Radiol 41:113-122
47. Al-Hawary MM, Francis IR, Korobkin M 2005 Non-invasive evaluation of the incidentally detected indeterminate adrenal mass. Best Pract Res Clin Endocrinol Metab 19:277-292
48. Boland GW, Goldberg MA, Lee MJ, Mayo-Smith WW, Dixon J, McNicholas MM, Mueller PR 1995 Indeterminate adrenal mass in patients with cancer: evaluation at PET with 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology 194: 131-134
49. Maurea S, Mainolfi C, Bazzicalupo L, Panico MR, Imparato C, Alfano B, Ziviello M, Salvatore M 1999 Imaging of adrenal tumors using FDG PET: comparison of benign and malignant lesions. AJR Am J Roentgenol 173:25-29
50. Yun M, Kim W, Alnafisi N, Lacorte L, Jang S, Alavi A 2001 18F-FDG PET in characterizing adrenal lesions detected on CT or MRI. J Nucl Med 42: 1795-1799
51. Becherer A, Vierhapper H, Potzi C, Karanikas G, Kurtaran A, Schmaljo- hann J, Staudenherz A, Dudczak R, Kletter K 2001 FDG-PET in adrenocor- tical carcinoma. Cancer Biother Radiopharm 16:289-295
52. Kumar R, Xiu Y, Yu JQ, Takalkar A, El-Haddad G, Potenta S, Kung J, Zhuang H, Alavi A 2004 18F-FDG PET in evaluation of adrenal lesions in patients with lung cancer. J Nucl Med 45:2058-2062
53. Jana S, Zhang T, Milstein DM, Isasi CR, Blaufox MD 2006 FDG-PET and CT characterization of adrenal lesions in cancer patients. Eur J Nucl Med Mol Imaging 33:29-35
54. Bergstrom M, Juhlin C, Bonasera TA, Sundin A, Rastad J, Akerstrom G, Langstrom B 2000 PET imaging of adrenal cortical tumors with the 118- hydroxylase tracer 11C-metomidate. J Nucl Med 41:275-282
55. Eriksson B, Bergstrom M, Sundin A, Juhlin C, Orlefors H, Oberg K, Lang- strom B 2002 The role of PET in localization of neuroendocrine and adre- nocortical tumors. Ann NY Acad Sci 970:159-169
56. Khan TS, Sundin A, Juhlin C, Langstrom B, Bergstrom M, Eriksson B 2003
11C-Metomidate PET imaging of adrenocortical cancer. Eur J Nucl Med Mol Imaging 30:403-410
57. Minn H, Salonen A, Friberg J, Roivainen A, Viljanen T, Langsjo J, Salmi J, Valimaki M, Nagren K, Nuutila P 2004 Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F-FDG. J Nucl Med 45:972-979
58. Zettinig G, Mitterhauser M, Wadsak W, Becherer A, Pirich C, Vierhapper H, Niederle B, Dudczak R, Kletter K 2004 Positron emission tomography imaging of adrenal masses: (18)F-fluorodeoxyglucose and the 11ß-hydrox- ylase tracer (11)C-metomidate. Eur J Nucl Med Mol Imaging 31:1224-1230
59. Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, Worden FP 2005 Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 12:667-680
60. Weiss LM, Medeiros LJ, Vickery Jr AL 1989 Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13:202-206
61. Goldblum JR, Shannon R, Kaldjian EP, Thiny M, Davenport R, Thompson N, Lloyd RV 1993 Immunohistochemical assessment of proliferative activity in adrenocortical neoplasms. Mod Pathol 6:663-668
62. Vargas MP, Vargas HI, Kleiner DE, Merino MJ 1997 Adrenocortical neo- plasms: role of prognostic markers MIB-1, P53, and RB. Am J Surg Pathol 21:556-562
63. Terzolo M, Boccuzzi A, Bovio S, Cappia S, De Giuli P, Ali A, Paccotti P, Porpiglia F, Fontana D, Angeli A 2001 Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors. Urology 57:176- 182
64. Wachenfeld C, Beuschlein F, Zwermann O, Mora P, Fassnacht M, Allolio B, Reincke M 2001 Discerning malignancy in adrenocortical tumors: are molecular markers useful? Eur J Endocrinol 145:335-341
65. Saeger W 2000 Histopathological classification of adrenal tumours. Eur J Clin Invest 30:58-62
66. Saeger W, Fassnacht M, Chita R, Prager G, Nies C, Lorenz K, Barlehner E, Simon D, Niederle B, Beuschlein F, Allolio B, Reincke M 2003 High diag- nostic accuracy of adrenal core biopsy: results of the German and Austrian adrenal network multicenter trial in 220 consecutive patients. Hum Pathol 34:180-186
67. Tissier F, Louvel A, Grabar S, Hagnere AM, Bertherat J, Vacher-Lavenu MC, Dousset B, Chapuis Y, Bertagna X, Gicquel C 2004 Cyclin E correlates with malignancy and adverse prognosis in adrenocortical tumors. Eur J Endocrinol 150:809-817
68. Macfarlane DA 1958 Cancer of the adrenal cortex: the natural history, prog- nosis and treatment in a study of fifty-five cases. Ann R C Surg Engl 23:155- 186
69. Bradley 3rd EL 1975 Primary and adjunctive therapy in carcinoma of the adrenal cortex. Surg Gynecol Obstet 141:507-516
70. Sullivan M, Boileau M, Hodges CV 1978 Adrenal cortical carcinoma. J Urol 120:660-665
71. Icard P, Chapuis Y, Andreassian B, Bernard A, Proye C 1992 Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112:972-979; discussion 979-980
72. Lee JE, Berger DH, el-Naggar AK, Hickey RC, Vassilopoulou-Sellin R, Gagel RF, Burgess MA, Evans DB 1995 Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118:1090-1098
73. DeLellis RA, Lloyd RV, Heitz PU, Eng C 2004 World Health Organization classification of tumours. Pathology and genetics of tumours of endocrine organs. Lyon, France; IARC Press
74. Hutter Jr AM, Kayhoe DE 1966 Adrenal cortical carcinoma. Clinical features of 138 patients. Am J Med 41:572-580
75. Didolkar MS, Bescher RA, Elias EG, Moore RH 1981 Natural history of adrenal cortical carcinoma: a clinicopathologic study of 42 patients. Cancer 47:2153-2161
76. Bellantone R, Ferrante A, Boscherini M, Lombardi CP, Crucitti P, Crucitti F, Favia G, Borrelli D, Boffi L, Capussotti L, Carbone G, Casaccia M, Cavallaro A, Del Gaudio A, Dettori G, Di Giovanni V, Mazziotti A, Mar- rano D, Masenti E, Miccoli P, Mosca F, Mussa A, Petronio R, Piat G, Marazano L, et al 1997 Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma. Surgery 122:1212-1218
77. Kendrick ML, Lloyd R, Erickson L, Farley DR, Grant CS, Thompson GB, Rowland C, Young Jr WF, van Heerden JA 2001 Adrenocortical carcinoma: surgical progress or status quo? Arch Surg 136:543-549
78. Gonzalez RJ, Shapiro S, Sarlis N, Vassilopoulou-Sellin R, Perrier ND, Evans DB, Lee JE 2005 Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery 138:1078-1085; discussion, 1085-1086
79. Mingoli A, Nardacchione F, Sgarzini G, Marzano M, Ciccarone F, Modini C 1996 Inferior vena cava involvement by a left side adrenocortical carcinoma: operative and prognostic considerations. Anticancer Res 16:3197-3200
80. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P 1996 The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitu- tional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119:161-170
81. Hedican SP, Marshall FF 1997 Adrenocortical carcinoma with intracaval extension. J Urol 158:2056-2061
82. Smith CD, Weber CJ, Amerson JR 1999 Laparoscopic adrenalectomy: new gold standard. World J Surg 23:389-396
83. Gill IS 2001 The case for laparoscopic adrenalectomy. J Urol 166:429-436
84. Saunders BD, Doherty GM 2004 Laparoscopic adrenalectomy for malignant disease. Lancet Oncol 5:718-726
85. Shen WT, Sturgeon C, Duh QY 2005 From incidentaloma to adrenocortical carcinoma: the surgical management of adrenal tumors. J Surg Oncol 89: 186-192
86. Cobb WS, Kercher KW, Sing RF, Heniford BT 2005 Laparoscopic adrenal- ectomy for malignancy. Am J Surg 189:405-411
87. Icard P, Louvel A, Chapuis Y 1992 Survival rates and prognostic factors in adrenocortical carcinoma. World J Surg 16:753-758
88. Zografos GC, Driscoll DL, Karakousis CP, Huben RP 1994 Adrenal ade- nocarcinoma: a review of 53 cases. J Surg Oncol 55:160-164
89. Jensen JC, Pass HI, Sindelar WF, Norton JA 1991 Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy. Arch Surg 126:457-461
90. Schulick RD, Brennan MF 1999 Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol 6:719-726
91. Wood BJ, Abraham J, Hvizda JL, Alexander HR, Fojo T 2003 Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 97:554-560
92. Rhim H, Dodd 3rd GD, Chintapalli KN, Wood BJ, Dupuy DE, Hvizda JL, Sewell PE, Goldberg SN 2004 Radiofrequency thermal ablation of abdominal tumors: lessons learned from complications. Radiographics 24:41-52
93. Brown DB 2005 Concepts, considerations, and concerns on the cutting edge of radiofrequency ablation. J Vasc Interv Radiol 16:597-613
94. Lipsett MB, Hertz R, Ross GT 1963 Clinical and pathophysiologic aspects of adrenocortical carcinoma. Am J Med 35:374-383
95. Schulick RD, Brennan MF 1999 Adrenocortical carcinoma. World J Urol 17:26-34
96. Percarpio B, Knowlton AH 1976 Radiation therapy of adrenal cortical car- cinoma. Acta Radiol Ther Phys Biol 15:288-292
97. King DR, Lack EE 1979 Adrenal cortical carcinoma: a clinical and pathologic study of 49 cases. Cancer 44:239-244
98. Henley DJ, van Heerden JA, Grant CS, Carney JA, Carpenter PC 1983 Adrenal cortical carcinoma-a continuing challenge. Surgery 94:926-931
99. Magee BJ, Gattamaneni HR, Pearson D 1987 Adrenal cortical carcinoma: survival after radiotherapy. Clin Radiol 38:587-588
100. Nader S, Hickey R, Sellin R, Samaan N 1983 Adrenal cortical carcinoma. A study of 77 cases. Cancer 52:707-711
101. Venkatesh S, Hickey RC, Sellin RV, Fernandez JF, Samaan NA 1989 Ad- renal cortical carcinoma. Cancer 64:765-769
102. Markoe AM, Serber W, Micaily B, Brady LW 1991 Radiation therapy for adjunctive treatment of adrenal cortical carcinoma. Am J Clin Oncol 14:170- 174
103. Pommier RF, Brennan MF 1992 An eleven-year experience with adrenocor- tical carcinoma. Surgery 112:963-970; discussion, 970-971
104. Stewart DR, Jones PH, Jolleys A 1974 Carcinoma of the adrenal gland in children. J Pediatr Surg 9:59-67
105. Ribeiro RC, Michalkiewicz EL, Figueiredo BC, DeLacerda L, Sandrini F, Pianovsky MD, Sampaio G, Sandrini R 2000 Adrenocortical tumors in children. Braz J Med Biol Res 33:1225-1234
106. Fassnacht M, Hahner S, Polat B, Koschker AC, Kenn W, Flentje M, Allolio B 2006 Adjuvant radiation therapy of the tumor bed prevents local recur- rences in adrenocortical carcinoma. Exp Clin Endocrinol Diabet 114:S17 (ab- stract P01-003)
107. Hahner S, Fassnacht M 2005 Mitotane for adrenocortical carcinoma treat- ment. Curr Opin Investig Drugs 6:386-394
108. Schteingart DE 2000 Conventional and novel strategies in the treatment of adrenocortical cancer. Braz J Med Biol Res 33:1197-1200
109. Bergenstal D, Lipsett M, Moy R, Hertz R 1959 Regression of adrenal cancer and suppression of adrenal function in men by o,p-DDD. Trans Am Physi- cians 72:341
110. Bergenstal DM, Hertz R, Lipsett MB, Moy RH 1960 Chemotherapy of ad- renocortical cancer with o,p’DDD. Ann Intern Med 53:672-682
111. Lubitz JA, Freeman L, Okun R 1973 Mitotane use in inoperable adrenal cortical carcinoma. JAMA 223:1109-1112
112. Becker D, Schumacher OP 1975 o,p’DDD therapy in invasive adrenocortical carcinoma. Ann Intern Med 82:677-679
113. Boven E, Vermorken JB, van Slooten H, Pinedo HM 1984 Complete response of metastasized adrenal cortical carcinoma with o,p’-DDD. Case report and literature review. Cancer 53:26-29
114. Krzisnik C, Petric G, Jereb B 1988 Complete response of metastatic adrenal cortical carcinoma to o,p’-DDD in a child. Pediatr Hematol Oncol 5:65-69
115. Lim MC, Tan YO, Chong PY, Cheah JS 1990 Treatment of adrenal cortical carcinoma with mitotane: outcome and complications. Ann Acad Med Sin- gapore 19:540-544
116. Decker RA, Kuehner ME 1991 Adrenocortical carcinoma. Am Surg 57:502- 513
117. Remond S, Bardet S, Charbonnel B 1992 [Complete and lasting remission of a metastatic malignant adrenocortical carcinoma under treatment with OP- ‘DDD alone]. Presse Med 21:865
118. Ilias I, Alevizaki M, Philippou G, Anastasiou E, Souvatzoglou A 2001 Sustained remission of metastatic adrenal carcinoma during long-term ad- ministration of low-dose mitotane. J Endocrinol Invest 24:532-535
119. Allolio B, Hahner S, Weismann D, Fassnacht M 2004 Management of ad- renocortical carcinoma. Clin Endocrinol (Oxf) 60:273-287
120. van Slooten H, Moolenaar AJ, van Seters AP, Smeenk D 1984 The treatment of adrenocortical carcinoma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol 20:47-53
121. Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM 1994 Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 69:947-951
122. Baudin E, Pellegriti G, Bonnay M, Penfornis A, Laplanche A, Vassal G, Schlumberger M 2001 Impact of monitoring plasma 1,1-dichlorodiphenil- dichloroethane (o,p’DDD) levels on the treatment of patients with adreno- cortical carcinoma. Cancer 92:1385-1392
123. Heilmann P, Wagner P, Nawroth PP, Ziegler R 2001 [Therapy of the adre- nocortical carcinoma with Lysodren (o,p’-DDD). Therapeutic management by monitoring o,p’-DDD blood levels]. Med Klin 96:371-377
124. Seki M, Nomura K, Hirohara D, Kanazawa M, Sawada T, Takasaki K, Demura H 1999 Changes in neoplastic cell features and sensitivity to mitotane during mitotane-induced remission in a patient with recurrent, metastatic adrenocortical carcinoma. Endocr Relat Cancer 6:529-533
125. Terzolo M, Pia A, Berruti A, Osella G, Ali A, Carbone V, Testa E, Dogliotti L, Angeli A 2000 Low-dose monitored mitotane treatment achieves the ther- apeutic range with manageable side effects in patients with adrenocortical cancer. J Clin Endocrinol Metab 85:2234-2238
126. Hutter Jr AM, Kayhoe DE 1966 Adrenal cortical carcinoma. Results of treat- ment with o,p’DDD in 138 patients. Am J Med 41:581-592
127. Schteingart DE, Motazedi A, Noonan RA, Thompson NW 1982 Treatment of adrenal carcinomas. Arch Surg 117:1142-1146
128. Lanser JB, van Seters AP, Moolenaar AJ, Haak HR, Bollen EL 1992 Neu- ropsychologic and neurologic side effects of mitotane and reversibility of symptoms. J Clin Oncol 10:1504
129. Bollen E, Lanser JB 1992 Reversible mental deterioration and neurological disturbances with o,p’-DDD therapy. Clin Neurol Neurosurg 94(Suppl):S49- S51
130. Hague RV, May W, Cullen DR 1989 Hepatic microsomal enzyme induction and adrenal crisis due to o,p’DDD therapy for metastatic adrenocortical carcinoma. Clin Endocrinol (Oxf) 31:51-57
131. Bertagna C, Orth DN 1981 Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med 71:855-875
132. Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, Cordon-Cardo C, Jaques DP, Brennan MF 2002 Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20:941-950
133. Dickstein G 1999 Is there a role of low dose of mitotane as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 84:1488-1489
134. Dickstein G, Shechner C, Arad E, Best LA, Nativ O 1998 Is there a role for low doses of mitotane (o,p’-DDD) as adjuvant therapy in adrenocortical carcinoma? J Clin Endocrinol Metab 83:3100-3103
135. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, Taylor SH, Hess KR, Schultz PN, Samaan NA 1993 Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71:3119-3123
136. Ahlman H, Khorram-Manesh A, Jansson S, Wangberg B, Nilsson O, Jacobsson CE, Lindstedt S 2001 Cytotoxic treatment of adrenocortical car- cinoma. World J Surg 25:927-933
137. Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L 2005 Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of ad-
vanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 12:657-666
138. Khan TS, Imam H, Juhlin C, Skogseid B, Grondal S, Tibblin S, Wilander E, Oberg K, Eriksson B 2000 Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol 11:1281-1287
139. Khan TS, Sundin A, Juhlin C, Wilander E, Oberg K, Eriksson B 2004 Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer. Med Oncol 21: 167-177
140. Abraham J, Bakke S, Rutt A, Meadows B, Merino M, Alexander R, Schrump D, Bartlett D, Choyke P, Robey R, Hung E, Steinberg SM, Bates S, Fojo T 2002 A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glyco- protein antagonist. Cancer 94:2333-2343
141. Bates SE, Shieh CY, Mickley LA, Dichek HL, Gazdar A, Loriaux DL, Fojo AT 1991 Mitotane enhances cytotoxicity of chemotherapy in cell lines ex- pressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas. J Clin Endocrinol Metab 73:18-29
142. Feller N, Hoekman K, Kuiper CM, Linn SC, Verheul HM, Wolthers BG, Popp-Snijders C, Pinedo HM 1997 A patient with adrenocortical carcinoma: characterization of its biological activity and drug resistance profile. Clin Cancer Res 3:389-394
143. Feldman D 1986 Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis. Endocr Rev 7:409-420
144. Miller JW, Crapo L 1993 The medical treatment of Cushing’s syndrome. Endocr Rev 14:443-458
145. Fassnacht M, Hahner S, Beuschlein F, Klink A, Reincke M, Allolio B 2000 New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line. Eur J Clin Invest 30(Suppl 3):76-82
146. Contreras P, Rojas A, Biagini L, Gonzalez P, Massardo T 1985 Regression of metastatic adrenal carcinoma during palliative ketoconazole treatment. Lancet 2:151-152
147. Allolio B, Schulte HM, Kaulen D, Reincke M, Jaursch-Hancke C, Winkel- mann W 1988 Nonhypnotic low-dose etomidate for rapid correction of hy- percortisolaemia in Cushing’s syndrome. Klin Wochenschr 66:361-364
148. Schulte HM, Benker G, Reinwein D, Sippell WG, Allolio B 1990 Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cush- ing’s syndrome and dose-response relationship in normal subjects. J Clin Endocrinol Metab 70:1426-1430
149. Wortsman J, Soler NG 1977 Mitotane. Spironolactone antagonism in Cush- ing’s syndrome. JAMA 238:2527
150. Leboulleux S, Dromain C, Bonniaud G, Auperin A, Caillou B, Lumbroso J, Sigal R, Baudin E, Schlumberger M 2006 Diagnostic and prognostic value of 18-fluorodeoxyglucose positron emission tomography in adrenocortical carcinoma: a prospective comparison with computed tomography. J Clin Endocrinol Metab 91:920-925
151. Soreide JA, Brabrand K, Thoresen SO 1992 Adrenal cortical carcinoma in Norway, 1970-1984. World J Surg 16:663-667; discussion, 668
152. Vassilopoulou-Sellin R, Schultz PN 2001 Adrenocortical carcinoma. Clinical outcome at the end of the 20th century. Cancer 92:1113-1121
153. Harrison LE, Gaudin PB, Brennan MF 1999 Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection. Arch Surg 134:181-185
154. Decker RA, Elson P, Hogan TF, Citrin DL, Westring DW, Banerjee TK, Gilchrist KW, Horton J 1991 Eastern Cooperative Oncology Group study 1879: mitotane and Adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110:1006-1013
155. Barzon L, Fallo F, Sonino N, Daniele O, Boscaro M 1997 Adrenocortical carcinoma: experience in 45 patients. Oncology 54:490-496
156. Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED 2000 Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adreno- cortical carcinoma: a Southwest Oncology Group Study. Cancer 88:1159-1165
JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.