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Adrenocortical Carcinoma: Clinical Update

Endocrinology and Diabetes Unit, Department of Medicine I, University Hospital Wuerzburg, 97080 Wuerzburg, Germany

Address all correspondence and requests for reprints to: Bruno Allolio, M.D., Endocrinology and Diabetes Unit, Department of Medicine I, University Hospital Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany. E-mail: allolio_b@medizin.uni-wuerzburg.de; or fassnacht_m{at}medizin.uni-wuerzburg.de.

	Abstract

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Context: Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with incompletely understood pathogenesis and poor prognosis. Patients present with hormone excess (e.g. virilization, 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: adrenal, 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 prognostic 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 optimum results. In advanced disease, the most promising therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane, and streptozotocin plus mitotane) are currently being compared in an international 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).

	Epidemiology

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ADRENOCORTICAL 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 variable but generally poor prognosis (3, 4, 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 incidence of 0.3 per 1 million children younger than 15 yr) and is related to a TP53 tumor suppressor gene mutation (6, 7, 8). Women are more often affected than men (ratio 1.5) (9, 10, 11, 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).

	Molecular Pathogenesis

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The molecular pathogenesis of ACC has been the topic of recent reviews (13, 14, 15, 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, 20, 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 frequently observed. In vitro experiments suggest that overexpressed IGF-II acting via the IGF-I receptor is relevant for adrenal cancer cell proliferation (22, 23, 24). Thus, the IGF-II IGF-I receptor pathway is a promising target for future therapies in ACC (25).

	Clinical Presentation

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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 autonomous 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 dehydroepiandrosterone sulfate (DHEA-S) is another clue suggesting ACC, whereas decreased serum DHEA-S concentrations are suggestive of a benign adenoma (26). Aldosterone-producing adrenocortical carcinomas present with hypertensionand 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-hydroxysteroid 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 androstenedione or 17-hydroxyprogesterone can often be demonstrated, thereby establishing the adrenocortical origin of the tumor.

Hormonally inactive ACCs usually present with abdominal 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 increasing percentage of ACCs is discovered as incidentaloma during abdominal imaging (28, 29, 30, 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

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Hormonal work-up

Careful endocrine assessment is mandatory prior to surgery 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, autonomous 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 incomplete 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 differentiate between ACC and pheochromocytoma (26).

Both size and appearance of an adrenal mass on computerized tomography (CT), magnetic resonance imaging (MRI), and more recently ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) have been used to distinguish between 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 neoplasia, 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 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 metaanalysis 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, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43) for carcinomas, indicating overlap between both groups (33). For better discrimination of lipid-poor adenomas from ACC, a delayed contrast-enhanced CT can be used, analyzing washout of contrast medium. Adrenal lesions with an attenuation value of more than 10 HU in unenhanced CT or an enhancement 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, 35, 36, 37, 38, 39, 40).

View larger version (151K): [in this window] [in a new window]   FIG. 1. CT of a large inhomogeneous ACC of the left adrenal gland with multiple pulmonary and hepatic metastases (see arrows) (image kindly provided by W. Kenn, Department of Radiology, University of Wuerzburg, Wuerzburg, Germany).

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 performance of FDG-PET in differentiating malignant from benign adrenal lesions in patients with proven or suspected malignancy (48, 49, 50, 51, 52, 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 adrenocortical origin from other lesions (54, 55, 56, 57, 58). It may be particularly 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 tumors 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 malignant 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

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Pathological diagnosis should be performed by an experienced pathologist. Differentiation between benign and malignant adrenal lesions is based on macroscopic features (tumor 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 characteristic feature separating ACC from benign tumors. Careful assessment of the R-status is of great importance but unfortunately still often missing in the pathology report.

Important additional information is gained from immunohistochemistry. Several studies have demonstrated the value of Ki67 staining in differentiating benign from malignant lesions (61, 62, 63, 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-, melan A, and chromogranin A are helpful to define or exclude 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 malignant adrenal lesions (67).

	Staging

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Until 2004, no official tumor nodes and metastasis (TNM) classification was available for ACC, and different staging systems were used (68, 69, 70, 71, 72), most often the Sullivan modification of the Macfarlane system. Accordingly, the new Union International Contre Cancer (UICC) staging system published 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, respectively. 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 presenting with distant metastases. However, the prognostic value of the different staging systems has never been compared 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 currently 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, 77, 78), most likely reflecting improved and more widely available imaging technology.

	Therapy (Fig. 2)

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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, 80, 81). In particular, an R0 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 compatible with complete tumor resection but occasionally necessitates cardiac bypass technique (5, 79, 81).

View larger version (27K): [in this window] [in a new window]   FIG. 2. Flow chart for patients with ACC. a, Adjuvant therapy should be considered in all patients with a high risk of recurrence (tumor size > 12 cm, high mitotic rate); b, mitotane drug monitoring required; c, after more than 2 yr of complete remission, imaging intervals may be prolonged; d, complete resection in stage IV should always be followed by adjuvant therapy; e, after consultation with a reference center. EDP, Etoposide, doxorubicin, cis-platin.

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 therapeutic options.

Surgery for local recurrences or metastatic disease is accepted 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 alternative 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, 97, 98, 99, 100, 101, 102, 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 (presumably 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 observations 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 recurrence, 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 exerts a specific cytotoxic effect on adrenocortical cells producing 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 covalently binds to macromolecules, predominantly mitochondrial 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 mitotane (107). In addition, oxidative damage through production 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 enzymes (107).

Several publications have established the impact of monitoring blood mitotane concentrations for predicting efficacy and toxicity. Although a threshold mitotane concentration of 14 mg/liter for antitumor response was defined retrospectively (120), this threshold has been confirmed in further studies (121, 122, 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 administration 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 tolerance, to 5–6 g/d. This high-dose regimen requires measurement of mitotane blood levels 14 d after initiation of therapy. Afterward, the dose is adjusted according to mitotane 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 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-hydroxytryptamine 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 glucocorticoid replacement (e.g. 50 mg hydrocortisone daily) is needed. Inadequate glucocorticoid substitution enhances mitotane-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 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 detrimental effect. In this study mitotane was offered to all patients after complete surgery between (n = 14) (135). Unexpectedly, 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 treatment option in ACC.

Cytotoxic chemotherapy. Experience with cytotoxic chemotherapy 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. However, only a minority of patients respond to current protocols, with the exception of a treatment regimen from Italy combining mitotane with etoposide, doxorubicin, and cisplatin. According to WHO criteria, the overall response rate in 72 patients was 49%, including five patients with complete response (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 reported a second-line cytotoxic chemotherapy regimen in 11 patients after failure of streptozotocin plus mitotane. Using a combination of vincristine, cisplatin, teniposide, and cyclophosphamide, 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 chemotherapy. This is the first study on a second-line chemotherapy in ACC including more than 10 patients demonstrating activity in a significant number of patients.

The success of both the Berruti protocol and the combination 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 Advanced 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-glycoprotein may therefore enhance the efficacy of cytotoxic therapy, and in vitro evidence that mitotane may reverse multidrug resistance has been the rationale to combine cytotoxic treatment with mitotane (141, 142). However, it remains uncertain to what extent mitotane also enhances tumor responsivity to cytotoxic drugs in vivo (140).

Treatment of hormone excess. Hypersecretion of hormonal steroids 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, osteoporotic 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 ketoconazole, 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 etomidate (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 adrenostatic drugs, close monitoring by an experienced endocrinologist 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

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In functioning tumors, hormonal markers should be measured 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 intervals 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 metastases (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 associated with advanced ACC and poor prognosis (132). However, these findings need confirmation in further studies.

Prognostic markers are of particular interest in patients after R0 resection to better define populations, which may or may not benefit from adjuvant treatment strategies.

	Structural Progress and Future Perspectives

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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 modified 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 compared 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 protocols 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 Network for the Study of Adrenal Tumors has been founded, interconnecting these national initiatives. It will provide a common database supported by a standardized tumor-banking 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 perspectives have led to new concepts and phase II trials in the United States recently reviewed in this journal (25). However, true progress will only follow a better understanding of the molecular pathogenesis of ACC. Variable clinical presentation and wide differences in biological behavior indicate significant heterogeneity of ACC. Thus, predicting tumor 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.

	Footnotes

 
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.

First Published Online March 21, 2006

Abbreviations: ACC, Adrenocortical carcinoma; CNS, central nervous system; CT, computerized tomography; DHEA-S, dehydroepiandrosterone sulfate; FDG-PET, ¹⁸F-fluorodeoxyglucose positron emission tomography; HU, Hounsfield unit; MRI, magnetic resonance imaging.

Received December 7, 2005.

Accepted March 9, 2006.

	References

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