ELSEVIER SAUNDERS
Adrenocortical Carcinoma
Steven E. Rodgers, MD, PHD, Douglas B. Evans, MD, Jeffrey E. Lee, MD, Nancy D. Perrier, MD*
Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 444, Houston, TX 77030, USA
Adrenocortical carcinoma (ACC) is a rare disease with a worldwide inci- dence of 0.5 to 2 per 1 million people annually [1,2]. It occurs most com- monly in adults in their fourth and fifth decades of life, with a mean age at diagnosis of between 43 and 49 years [3-6]; however, there is another, smaller peak in children younger than 5 years old [7]. A slightly higher in- cidence rate is reported for women than for men. In a 1996 study of risk fac- tors, cigarette smoking and the use of oral contraceptives were found to be associated with the development of ACC [8]. An association has also been found between ACC and congenital adrenal hyperplasia [9,10].
Bartholomew Eustachius, the Italian anatomist, is credited with first de- scribing the adrenal gland, in 1563. However, little was understood of this organ’s function for the next 300 years. Although benign and metastatic tumors of the adrenal gland were known to be relatively common, primary malignant tumors of the adrenal cortex were reported only occasionally, beginning in the early twentieth century. Reporting in the Chinese Medical Journal in 1940, Wu [11] found only 82 cases of ACC described in the lit- erature. In 1958, Macfarlane [12] published a series of 55 cases with can- cer of the adrenal cortex. These patients had a mean age at diagnosis of 32 years and a female-to-male ratio of 1.3:1. The subjects in this series pre- sented with advanced disease: 62% had metastatic disease, and most of the lesions were large (up to 30 cm). In more recent literature, 18% to 39% of subjects present with evidence of distant metastases, and mean tumor size at the time of presentation varies from 12 cm to 14 cm (Table 1) [3-5].
* Corresponding author. E-mail address: nperrier@mdanderson.org (N.D. Perrier).
| Investigator | Year | No. patients | Avg. age | Avg. size of tumor (cm) | % With metastases | % 5-Yr survival (all patients) | % 5-Yr survival (post resection) |
|---|---|---|---|---|---|---|---|
| Icard et al [4] | 2001 | 253 | 47 | 12 | 21 | 38 | 50 |
| Schulick and Brennan [5] | 1999 | 113 | 43 | 14 | 39 | 37 | 55 |
| Crucitti et al [3] | 1995 | 129 | 49 | – | 18 | 35 | 48 |
Clinical presentation
In adults, approximately 60% of ACCs are functional, and patients pres- ent with symptoms of adrenocortical hormone excess. The most common clinical presentation is that of Cushing’s syndrome (present in 30%-40% of cases), caused by excess production of cortisol; this may also be seen in combination with virilization because of hypersecretion of androgens [13]. Cushing’s syndrome is characterized by truncal obesity, a rounded face (moon facies), purple striae on the abdominal wall, muscle weakness, and the development of diabetes mellitus (Fig. 1). Overproduction of androgens may go unnoticed in males; however, in females it produces hirsutism, a deepened voice, menstrual irregularity, and male pattern baldness. Excess production of estrogen is relatively rare. When it occurs in females, it may produce menstrual irregularity and breast tenderness, but more often re- mains clinically silent. When estrogen overproduction occurs in males, how- ever, a syndrome of feminization is seen, resulting in impotence, decreased libido, testicular atrophy, and gynecomastia [14,15]. True production of al- dosterone by ACC is less common (occurring in 3%-11% of all ACCs) [4,5,16]. When it does occur, it results in hypertension and hypokalemia. However, these same symptoms can be caused by severe Cushing’s syn- drome, in which excess levels of cortisol stimulate the mineralocorticoid re- ceptor [17]. ACCs are more often functional in children (90% of cases) than in adults. Most of these tumors produce androgens, leading to precocious puberty and virilization [18].
Patients with nonfunctional tumors typically present with abdominal pain, early satiety, weight loss, nausea and vomiting, or a palpable abdom- inal mass. Testicular pain and varicocele may also signal the presence of an adrenal mass. Nonfunctional tumors are typically larger at presentation than functional tumors, and a significant number are discovered incidentally during abdominal or thoracic imaging for other reasons. Some patients with nonfunctional tumors will remain asymptomatic until they present with signs or symptoms of metastatic disease (eg, jaundice, bone pain). Distant metastases develop most frequently in liver (42%-46% of cases), lung (45%-53% of cases), and lymph nodes (18%-40% of cases) [1,19,20].
Survival
In 1958, Macfarlane [12] reported a mean survival of only 2.9 months among 20 patients with ACC who received no treatment. More recently, a mean overall survival of 6 months was reported in patients with unresect- able tumors treated palliatively [21]. Several recently published studies (see Table 1) reported 5-year survival rates of 35% to 38% for all patients with ACC, and 5-year survival rates of 48% to 55% for those patients who underwent curative resection [3-5]. In a report of 40 children from Bra- zil with ACC, similar survival statistics were reported for those 7 years old or younger who underwent curative resection (50% 5-year survival) [22]. For reasons that are unclear, children older than 7 years demonstrated a markedly decreased long-term survival (17% 5-year survival). The inves- tigators speculated that ACC in children 7 years of age or younger (infantile ACC) represents a different disease process than ACC in children over 7 years old, and that this latter group may have an atypical or aggressive form of adult ACC. Comparison of overall survival and disease-free survival between patients with large ACCs (≥5 cm) and small ACCs (<5 cm) at the time of presentation shows no significant difference [23]. The major factors that do appear to affect survival are tumor stage at the time of diagnosis and completeness of resection [4,5].
Genetics
Several studies on the clonality of adrenocortical tumors have demon- strated that most benign adrenocortical lesions are polyclonal; however, all ACCs studied were monoclonal, suggesting that ACC develops through uncontrolled growth of a single cell [24,25]. Although the molecular patho- genesis of ACC is still poorly understood, in the last 2 decades much has been learned from studies of several hereditary syndromes associated with the development of adrenocortical tumors.
Li-Fraumeni syndrome (LFS) is an autosomal-dominant inherited cancer syndrome associated with a variety of malignant tumors, including soft-tis- sue sarcomas, osteosarcomas, breast cancer, leukemia, and pancreatic can- cer [24]. Approximately 1% of patients with LFS develop ACC, generally before the age of 30 [26]. As many as 70% of patients with LFS, including those with ACC, have identifiable germline mutations in the p53 gene [27], a tumor suppressor gene involved in cell cycle regulation and apoptosis. In- activating mutations of p53 have been linked to the development of tumors in almost every tissue type. Mutations of the p53 gene have also been found in patients with sporadic cases of ACC [28]. In a recent study, germline p53 mutations were identified in three of six children with sporadic ACC; these children were from families with no known history of LFS [29].
Beckwith-Wiedemann syndrome is another hereditary syndrome associ- ated with the development of ACC. It involves abnormal expression of the in- sulin-like growth factor II (IGF2) gene and is characterized by macroglossia, abdominal wall defects, rhabdomyosarcoma, and Wilms’ tumor. The IGF2 gene and several closely related regulatory genes belong to a small group of “imprinted” genes, or genes for which only one parentally derived copy is nor- mally expressed. The IGF2 gene is imprinted normally on the paternal copy of the gene locus, whereas its regulatory genes are imprinted on the maternal copy. In Beckwith-Wiedemann syndrome, the IGF2 gene becomes overex- pressed because the maternal copy of the IGF2 locus is inactivated, removing the necessary inhibitory control over IGF2 production [24]. A similar situa- tion is found in many sporadic cases of ACC, in which the paternal copy of the IGF2 locus is duplicated or the maternal copy inactivated within the tumor tissue [30]. How overexpression of IGF2 is related to the development of ACC is still unclear; however, there are large numbers of IGF2 receptors in adreno- cortical tissue, and it is believed that IGF2 exerts local autocrine and paracrine effects, leading to tumor progression [31,32].
During embryological development, exposure of adrenal tissue to adre- nocorticotropic hormone (ACTH) leads to differentiation of cells within the adrenal cortex. Additionally, evidence from a mouse model suggests that ACTH can inhibit the growth of ACC, possibly by maintaining cells in a well-differentiated state. This effect appears to be mediated through the ACTH receptor (ACTH-R) [33]. No inactivating mutations of the ACTH-R gene have been found in patients with ACC; however, loss of
heterozygosity (LOH), with significantly reduced expression of ACTH-R mRNA, was seen in two of four ACC patients studied. Furthermore, the two patients with the LOH mutations displayed a more rapid disease course than those without the LOH mutations [34].
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant inherited syndrome associated with the development of pituitary tumors, pancreatic endocrine tumors, and hyperparathyroidism. In addition, up to 35% of MEN1 patients develop adrenal nodules [35,36]. In a study of 67 German patients with MEN1, 18 (27%) were found to have adrenal tumors. Of these 18 patients, 4 developed ACC [37]. The exact role of the MEN1 gene and its protein product (menin) in the development of ACC is still un- clear; however, the MEN1 gene appears to be a tumor suppressor gene, and mutations within specific regions of this gene (exons 2 and 10) correlate with the development of adrenal tumors.
Diagnosis
Whenever an adrenal tumor is discovered or suspected, hormonal evalu- ation should be undertaken. Appropriate biochemical analysis should focus on the detection of excess cortisol, androgens or estrogens, aldosterone, and catecholamines. A higher percentage of ACCs are functional, compared with benign adrenal tumors, and hormonal analysis may aid occasionally in the differentiation of benign from malignant lesions.
Cortisol is the hormone most frequently overexpressed by adrenocortical tumors, including ACC. In many cases, Cushing’s syndrome, resulting from overexpression of cortisol, will be clinically obvious. This diagnosis can of- ten be confirmed by a grossly elevated urine-free cortisol level (on 24-hour urine collection) or plasma-free cortisol level. A more sensitive test for over- production of cortisol is the overnight low-dose dexamethasone suppression test. This involves administering 1 mg of dexamethasone orally at bedtime and measuring plasma-free cortisol the following morning. A normal re- sponse will result in a suppressed plasma cortisol level of 3 ug/dl or less. Failure of dexamethasone to suppress the plasma cortisol level (plasma- free cortisol >3 ug/dl) supports a diagnosis of autonomous cortisol pro- duction (ie, Cushing’s syndrome); however, the false-positive rate for this test may be as high as 30%.
Androgens and estrogens are the next most common class of hormones produced by ACC. When an adrenogenital syndrome (virilization or femini- zation) is suspected in a patient with an adrenal mass, initial biochemical analysis should include measurement of urine 17-ketosteroids following a 24-hour urine collection. Further investigation may include measure- ment of serum dehydroepiandrosterone (DHEA) and its sulfate deriva- tive DHEAS, 45-androstenediol, 44-androstenedione, testosterone, and 5a-dihydrotestosterone. Patients with hypertension and hypokalemia
should undergo measurement of serum aldosterone levels. In a study of 15 patients with aldosterone-secreting ACCs, the mean serum aldosterone level was 78 ng/dl (range, 15-136 ng/dl; normal, 1-21 ng/dl) [16]. Pure aldoste- rone hypersecretion occurred in 10 of these patients, whereas the remaining five subjects had both aldosterone and cortisol hypersecretion. Hypertension and hypokalemia were present in all 15 patients. Evidence of production of more than one adrenocortical hormone is highly suggestive of ACC, because benign tumors generally do not produce multiple hormones.
Every patient with an adrenal mass should be assessed for excess cate- cholamine production to rule out pheochromocytoma. Traditionally, this assessment is performed by measuring urine vanillylmandelic acid, urine metanephrines, and urine catecholamines after a 24-hour urine collection. However, measurement of plasma-free metanephrines has been shown to have a higher sensitivity (99%) for detection of pheochromocytoma than any other commonly available test [38]. Additionally, this simple blood test is easier to perform than a 24-hour urine collection.
Imaging
CT continues to be the initial imaging modality of choice for the diagno- sis and characterization of adrenal tumors. Adrenocortical adenomas typically have a high lipid content. When imaged using non-contrast- enhanced CT, the high lipid content imparts low attenuation values, mea- sured in Hounsfield units (HU). Lesions with attenuation values of less than or equal to 10 HU are virtually always benign adenomas, whereas le- sions with attenuation values of greater than 30 HU are consistently non- adenomas (ie, ACCs, metastatic lesions, or pheochromocytomas). Those lesions with intermediate attenuation values (between 10 and 30 HU) are usually adenomas, but must be evaluated carefully, based on other imaging characteristics [39]. On contrast-enhanced CT, ACCs often appear heteroge- neous and have irregular borders; calcifications are seen occasionally (Fig. 2). Any evidence of local invasion or nodal metastasis supports the di- agnosis of ACC.
With recent advances in technology, MRI has become popular as a method of characterizing adrenal lesions. The MRI appearance of ACC on T1-weighted images is hypointense relative to liver, whereas on T2- weighted images, ACC is hyperintense relative to liver. One of the advan- tages of MRI is its multiplanar capability, which allows demonstration of the invasion of ACC into surrounding structures, particularly the inferior vena cava. Evidence suggests that gadolinium-enhanced dynamic MRI is better than standard MRI for differentiating between benign and malignant adrenal tumors [40]. Adenomas demonstrate mild enhancement with a rapid washout, whereas ACCs and other nonadenomatous lesions show strong en- hancement with a slower washout. Chemical-shift MRI takes advantage of differences in the water/fat ratio of various adrenal lesions. As with CT,
adenomas are identified readily by their high lipid content. This technique has gained popularity in recent years as an adjunct to standard MRI.
In some centers, nuclear scintigraphy using cholesterol analogs such as iodine-131-6ß-iodomethyl-19-norcholesterol (NP-59) is employed to evalu- ate adrenal lesions. Many functional adrenocortical tumors will take up NP-59, but this feature does not differentiate benign from malignant lesions. Additionally, NP-59 is not widely available. Positron emission tomography (PET) has shown promising results in the imaging of adrenal tumors and is perhaps most useful for the detection of metastases; however, drawbacks include its expense and lack of universal availability. Also, benign pheochro- mocytomas are often positive on PET, suggesting malignancy and thus confounding their accurate diagnosis.
Size
Perhaps the single most significant predictor of malignancy in adrenocor- tical tumors is size. Most ACCs are more than 6 cm in diameter at the time of diagnosis [41]. In contrast, adrenal masses of less than 4 cm in diameter are generally benign. These data have been incorporated into National Institutes of Health consensus criteria, which include a recommendation that any adrenal mass of greater than 6 cm in diameter be resected, regard- less of its functional status or imaging characteristics [42]. However, a review of the literature over a 30-year period found that 9% of ACCs reported (in 44 of 488 subjects) were less than 5 cm in diameter at the time of diagnosis [43]. Because of the poor prognosis associated with delayed diagnosis or in- complete resection of ACC, many surgeons have, therefore, chosen to resect all lesions greater than 4 cm to 5 cm in size in patients who are good surgical candidates. Additionally, smaller lesions with suspicious characteristics (eg, heterogeneity on imaging, irregular borders, evidence of local invasion) probably should be treated as ACCs, unless proven otherwise. Therefore,
adrenal tumors that should be resected include those that are functional, those with suspicious imaging characteristics, and those greater than 4 cm to 5 cm in diameter. Use of these criteria leads to appropriate treatment (ie, surgical resection by means of an open approach) for the vast majority of ACCs.
Fine needle aspiration & biopsy
Fine needle aspiration (FNA) and percutaneous biopsy of adrenal tu- mors suspicious for ACC generally are contraindicated because of the risk of tumor seeding of the biopsy track. However, FNA may be performed in patients thought to have adrenal metastases from a known primary ma- lignancy, especially when results indicating metastatic disease would result in nonoperative therapy. FNA should not be performed until pheochromo- cytoma has been ruled out because of the risk of triggering a severe hyper- tensive crisis.
Staging
In his landmark 1958 study of 55 patients with ACC, David Macfarlane [12] proposed a staging system based on tumor size (≤5 cm or >5 cm in diameter), the presence of local invasion, and the involvement of regional lymph nodes. This system was later modified by Sullivan and colleagues [44] and has been adopted widely by clinicians treating patients with ACC. Further modifications of this tumor-node-metastasis (TNM) classifi- cation system have been proposed by Icard and colleagues [21] and Lee and colleagues [45]. The most significant change in these recent modifications is the classification of patients with invasion of adjacent organs (in the absence of distant metastasis) as stage III, and the classification of only patients with distant metastases as stage IV (Table 2). Although these modifications have not been accepted universally, they are more consistent with modern TNM classification systems for other cancers and more accurately predict survival.
Histopathology
The hallmarks of carcinoma that lead to a diagnosis of ACC include large size with irregular margins (Fig. 3), invasion of surrounding structures, and the presence of distant metastases; however, these are relatively nonspecific characteristics and are frequently absent in early disease, making it difficult to discriminate ACCs from benign adrenal tumors (ie, atypical adrenocorti- cal adenomas and pheochromocytomas). The histopathologic diagnosis of ACC continues to pose a challenge for the pathologist. In 1984, Louis Weiss, [46] from the Albert Einstein College of Medicine, proposed a histopathologic classification system for adrenocortical tumors, based on nine criteria. These include nuclear grade; number of mitoses; presence of atypical mitoses;
| Stage | Sullivan et al [44] | Lee et al [45] | ||
|---|---|---|---|---|
| I | T1 | T1 | ||
| N0 | N0 | |||
| M0 | M0 | |||
| II | T2 | T2 | ||
| N0 | N0 | |||
| M0 | M0 | |||
| III | T1-2 or | T3 | T3/T4 or | Any T |
| N1 | N0 | Any N | N1/N2 | |
| M0 | M0 | M0 | M0 | |
| IV | T4 or | Any T | Any T | |
| N2 | Any N | Any N | ||
| M0 | M1 | M1 | ||
Abbreviations: M0, no distant metastases; M1, distance metastases; N, node; N0, no nodal involvement; N1, involved nodes (mobile); N2, involved nodes (fixed); T, tumor; T1, tumor ≤5 cm; T2, tumor > 5cm; T3, local infiltration reaching neighboring organs; T4, invasion of neighboring organs.
percentage of clear cells; diffuse architecture; microscopic necrosis; and inva- sion of venous, sinusoidal, and capsular structures (Box 1). Using this system to classify 43 adrenocortical tumors, Weiss found that the presence of fewer than three of these criteria was always associated with benign tumors (100% of 24 tumors studied), whereas the presence of more than three of the criteria was associated with ACC in 18 of 19 tumors studied (95%). Despite wide- spread use of this grading system, poorly differentiated ACC may still be con- fused with renal cell carcinoma, small cell lung carcinoma, melanoma, or hepatocellular carcinoma. Similar but less widely adopted histopathologic grading systems have been developed for ACC by Hough and colleagues [47] and van Slooten and associates [48].
1
2
3
4
5
6
7
U
0
10
11
12
3
14
15
4
6
1
2
3
4
5
Box 1. Criteria used in Weiss classification system for adrenocortical tumorsª
Nuclear grade (III or IV) Number of mitoses (>5/50 high-power fields)
Presence of atypical mitoses Percentage of clear cells (≤25% of tumor)
Diffuse architecture Microscopic necrosis Venous invasion Sinusoidal invasion
Capsular invasion
a >3 of the above is consistent with ACC; < 3 indicates benign lesion. Data from Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-9.
Numerous molecular markers have been studied for possible use in the diagnosis of ACC, but few have shown any promise. One exception is the proliferation-associated antigen Ki67. More than 5% immunopositivity fol- lowing staining with a Ki67-specific monoclonal antibody is highly sugges- tive of ACC [49]. Also, a monoclonal antibody designated D11, which is directed against a 59-kDa human liver membrane protein, has been studied extensively for use in the differential diagnosis of adrenocortical neoplasms [50,51]. Immunohistochemical analysis using the D11 antibody is useful in the classification of adrenocortical neoplasms as benign (adenoma or hyper- plasia), malignant (ACC), or metastatic; furthermore, D11 positivity allows identification of well-differentiated ACCs, which may exhibit a more indo- lent clinical course [51].
Recently, 20 adrenocortical neoplasms (13 adenomas and 7 ACCs) were studied using complementary DNA microarrays to create transcriptional profiles [52]. This technique creates a specific molecular signature for each tumor and thereby allows adenomas and carcinomas to be distinguished clearly. These transcriptional profiles have identified specific genes that are upregulated and downregulated in ACC. Upregulated genes include several IGF-related genes (IGF2, IGF2R, IGFBP3, and IGFBP6) and two ubiquitin- related genes (USP4 and UFD1L). Genes that are downregulated include the cytokine gene CXCL10, the cadherin 2 gene (CDH2), and several genes re- lated to cell metabolism (RARRES2, ALDH1A1, CYBRD1, and GSTA4). The finding that numerous IGF-related genes are upregulated is consistent with what is known about the role of IGF2 in the pathogenesis of ACC (see Genetics section, above). This method of transcriptional profiling is cur- rently too labor intensive and costly for use in routine diagnosis of
adrenocortical tumors; however, it has opened numerous avenues for further research.
Treatment
Surgery
Complete surgical resection remains the only curative treatment for ACC. Unfortunately, more than 65% of ACCs are unresectable at the time of presentation [53]. The goal of surgery should be a complete mar- gin-negative resection with no violation of the tumor capsule to avoid tumor seeding in the retroperitoneum and abdominal cavity. Invasion of surround- ing structures may require en bloc resection of the kidney, liver, diaphragm, pancreas, spleen, or bowel. Typically, wide exposure is needed to achieve these goals, frequently requiring an extended subcostal incision or a thora- coabdominal approach. On occasion, tumor thrombus extends into the re- nal vein, the inferior vena cava, and even the right atrium. In rare cases, complete extirpation of tumor may require cardiopulmonary bypass and ex- tensive venous reconstruction. Several cases of long-term survival following successful removal of inferior vena cava tumor thrombus have been re- ported [54]. The role of noncurative resection of ACC is controversial. Sur- vival after incomplete resection remains poor [3,4,45]. However, there may be a role for palliative resection to diminish hormone production in those patients whose disease is controlled poorly by medical therapy.
Most surgeons have been reluctant to treat ACC with laparoscopic adre- nalectomy for fear of seeding the abdomen with malignant cells, resulting in peritoneal carcinomatosis. A recent study comparing laparoscopic with open adrenalectomy for the treatment of ACC showed that laparoscopic ad- renalectomy was associated with the development of local recurrence in three (50%) of six cases and peritoneal carcinomatosis in five (83%) of six cases). In contrast, only 46 (35%) of 133 cases treated with open adrenalec- tomy developed local recurrence, and only 11 (8%) of 133 cases developed carcinomatosis [55]. The high incidence of local recurrence and carcinoma- tosis associated with laparoscopic resection occurred despite the fact that the average size of the adrenal tumors resected laparoscopically was only half that of tumors resected by means of an open procedure (6 cm and 13 cm, respectively). These data underscore the necessity for identification of ACCs before surgical resection, so that the appropriate open surgical tech- nique can be employed.
Surgical resection of recurrent disease and isolated metastatic disease is a reasonable treatment option for highly selected patients. Some data sug- gest a significant improvement in patient survival following resection of re- current tumors and metastases, provided that complete (margin-negative) resection is possible [5]. Generally, complete resection is more likely to be achieved for discrete metastatic lesions than for local recurrences. For
patients with unresectable lesions (either primary or recurrent) or those who are poor surgical candidates, radiofrequency ablation of ACC has been used with encouraging preliminary results [56]. However, it is not yet clear if such ablative techniques will improve patient survival.
Cytotoxic therapy
Because of the large proportion of patients with ACC who present with advanced, unresectable disease, and the high recurrence rate following sur- gical resection, many patients will ultimately be candidates for systemic ther- apy. In 1960, Bergenstal and colleagues [57] first described the use of mitotane for the treatment of ACC. Mitotane, or o,p’-DDD, is a derivative of the insecticide DDT (Fig. 4). It had been observed that animals exposed to mitotane suffered from adrenal insufficiency. On further investigation, it was found that this agent was cytotoxic to adrenal tissue. When used to treat patients with ACC, a significant decrease in symptoms and objective tumor regression were seen in some cases. Initial reports of tumor response to mi- totane were as high as 61% [58]; more recent studies suggest either stabili- zation of disease or a clinical response in 4% to 35% of subjects [19,53,59-61]. These rates vary in part because of a lack of uniformity in the definition of clinical response and an inconsistency in the achievement of therapeutic mitotane levels. Patients who respond may demonstrate a de- crease in the size of their tumor, an improvement in their symptoms because of a reduction in hormone secretion, or both. Response rates appear to cor- relate with serum mitotane levels, although occasional dramatic responses may be seen in patients with mitotane levels traditionally thought to be sub- therapeutic. The proportion of patients who respond increases as serum levels rise above 10 µg/ml to 14 µg/ml [62]. For this reason, monitoring se- rum mitotane levels is important. Typically, 2 to 5 g/day are required to maintain therapeutic serum levels.
In a 1984 Dutch study of 34 patients with metastatic or recurrent ACC treated with mitotane, there was evidence of improved survival in those
CCI3
CI
CI
Dichlorodiphenyltrichloroethane (DDT)
CI
CI
CI
CI
2,4’-Dichlorodiphenyldichloroethane (o,p’-DDD; Mitotane)
subjects who maintained elevated serum drug levels for extended periods of time [62]. These data and anecdotal reports of disease remission for up to 17 years with mitotane treatment [63] have suggested there may be a role for mitotane therapy in treating ACC patients in the adjuvant setting. However, studies that have addressed adjuvant mitotane therapy have been unable to show improvements in patient survival [19,20,64,65]. Adequately designed prospective randomized trials are needed to understand better the benefit of mitotane for the treatment of ACC; because of the rare nature of the dis- ease, multi-institutional, international cooperation will be required.
The administration of mitotane in patients with ACC is complicated by its numerous adverse effects, including neuropsychiatric symptoms (head- ache, mood changes, somnolence, and visual disturbances); gastrointestinal side-effects (nausea and decreased appetite); muscle aches; and fatigue. Also, mitotane is fat soluble, has a very slow onset of action, and a significant “de- pot effect”; thus, several months are required to achieve therapeutic serum levels [66]. Because mitotane induces adrenal insufficiency, long-term ther- apy with this drug requires concomitant administration of an exogenous glucocorticoid (eg, hydrocortisone or dexamethasone) and mineralocorti- coid (eg, fludrocortisone). Typically, these agents must be given at levels higher than usually required for physiologic replacement because mitotane also alters the metabolism of exogenously administered steroids. Finally, long-term administration of mitotane requires monitoring of liver function, thyroid function, and serum lipid levels.
Numerous chemotherapeutic agents have been used to treat ACC, with disappointing results. Although most agents have shown little activity, doxorubicin has provided modestly encouraging results, either as a single agent or in combination with other agents [67,68]. Multidrug resistance me- diated through the MDR-1 gene is believed to play a pivotal role in the poor response of ACC to conventional chemotherapy, and high levels of the MDR-1 protein product (p-glycoprotein) have been found in ACCs [69,70]. Mitotane has been shown to inhibit the activity of p-glycoprotein, leading to increased cytotoxicity of chemotherapeutic agents [71]. For this reason, conventional chemotherapeutic regimens are often combined with mitotane. In a 2005 study by Berruti and colleagues [72], mitotane was used in combination with etoposide, doxorubicin, and cisplatin to treat patients with unresectable ACC; 28% of patients demonstrated stabilization of their disease, whereas 49% showed an objective response to treatment. Furthermore, 7% of subjects had a complete clinical response. These findings are encouraging and may lead to an improvement in the survival of patients with recurrent and metastatic ACC.
In 1987, researchers at the University of Cologne used suramin to treat a subject with metastatic ACC unresponsive to mitotane or traditional che- motherapeutic regimens [73]. Treatment with suramin led to an almost com- plete regression of lung metastases in this subject for a period of 4 months. This finding created interest in the use of suramin as an alternative treatment
in patients with unresectable and metastatic ACC. Suramin is an antitrypa- nosomal drug developed in the early 1900s and used in the treatment of Af- rican sleeping sickness and river blindness. During investigation of its use as an anti-HIV drug, it was found to cause regression of some HIV-associated cancers. Suramin has been found to inhibit the action of several growth fac- tors, including epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor. Additionally, suramin lowers serum levels of IGF1 and IGF2 [74], providing a possible mechanism of action against ACC (see Genetics section, above). Unfortunately, the anti-ACC ef- fects of suramin appear to be fairly transient, and its clinical use is limited by a very narrow therapeutic window [75].
Another antineoplastic compound that has attracted attention for the treatment of ACC is gossypol. Produced by the cotton plant (Gossypium sp.), gossypol is a naturally occurring insecticide that has been studied ex- tensively for use as a male contraceptive. It has been found to inhibit the growth of numerous cancer cell lines, including a human ACC cell line [76]. When used to treat patients with ACC, however, partial tumor re- sponses were observed in only a small number of cases. This poor response rate and the fact that several patients died during treatment have diminished interest in gossypol as a therapy for patients with ACC [77].
Endocrine therapy
Numerous drug regimens have been used for symptomatic relief in pa- tients suffering from the effects of excessive hormone production caused by functioning ACCs that are refractory to mitotane. Etomidate, aminoglu- tethimide, metyrapone, and ketoconazole have all been used with some suc- cess in patients with hypercortisolism. Nonsedating, low doses of etomidate can produce a rapid decline in serum cortisol levels and may be useful in the acute setting [78]. However, the fact that etomidate must be administered in- travenously limits its clinical usefulness to the inpatient setting. Aminoglu- tethimide is an anticonvulsant drug that inhibits conversion of cholesterol to pregnenolone, thereby decreasing the production of aldosterone, cortisol, and androgens. Although aminoglutethimide has been shown to lower cor- tisol levels in patients with ACC, its clinical usefulness appears limited by side-effects, including hypothyroidism, rash, and pruritus [79].
Metyrapone is a pyridine derivative that inhibits 11ß-hydroxylase, pre- venting the conversion of 11-deoxycortisol to cortisol. In a 1991 study of the efficacy of metyrapone for the treatment of Cushing’s syndrome, Ver- helst and colleagues [80] demonstrated a decrease in serum cortisol levels to below 14 µg/dl in 13 (81%) of 16 cases and a decrease to below 10 µg/dl in 7 (47%) of 15 cases with adrenocortical tumors. Side-effects experienced by these patients included hirsutism, dizziness, nausea, and rash.
Like metyrapone, ketoconazole inhibits 11ß-hydroxylase, blocking production of cortisol. Additionally, ketoconazole interferes with the
production of mineralocorticoids (aldosterone) and androgens. In a 1985 re- port from Chile, a subject with metastatic ACC treated with ketoconazole showed not only a significant decrease in tumor steroidogenesis, but also near complete regression of multiple lung metastases after 4 months of treat- ment [81]. Unfortunately, there are few other documented cases of clinical efficacy for this drug in patients with ACC, despite the fact that ketocona- zole is effective in the treatment of other causes of Cushing’s syndrome (eg, Cushing’s disease, adrenal adenomas, adrenal hyperplasia, and ectopic ACTH production) [82-84]. Overall, ketoconazole is well tolerated. The most common side-effect is hepatotoxicity, which occurs in approximately 12% of patients [85].
Adjuvant radiation
Despite anecdotal evidence of improved survival in selected patients [6,63], radiotherapy for the treatment of primary ACC is considered to be of limited benefit. At the authors’ institution, in a series of 19 patients who received external beam radiation for abdominal disease or local recur- rence, only 3 (16%) of 19 cases demonstrated a response, defined as a de- crease in the size of the mass. Survival in all subjects was less than 2 years from the onset of treatment [6]. Radiotherapy is advocated at some centers for treatment of the adrenal bed postoperatively to reduce local recurrence. There is a consensus that radiotherapy is appropriate for palliative treat- ment of bony metastases and as a component of therapy for patients with brain metastases.
Summary
ACC is a rare clinical entity that carries a poor prognosis; early diagnosis and complete surgical resection are associated with improvement in patient survival. Even with appropriate diagnosis and treatment, most patients will develop recurrence and succumb to ACC because of the underlying tumor biology, the difficulty of achieving a complete resection, and the lack of ef- fective systemic therapies. Despite its many drawbacks, mitotane continues to be a mainstay in the treatment of high-risk patients with ACC, especially those with recurrent or metastatic disease. Recent findings suggest that mi- totane, combined with conventional chemotherapeutic agents, may improve survival for such patients.
References
[1] Brennan MF. Adrenocortical carcinoma. CA Cancer J Clin 1987;37:348-65.
[2] National Cancer Institute. Third national cancer survey: incidence data. Natl Cancer Inst Monogr 1975;41:1-454.
[3] Crucitti F, Bellantone R, Ferrante A, et al. The Italian Registry for Adrenal Cortical Carci- noma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 1996;119:161-70.
[4] Icard P, Goudet P, Charpenay C, et al. Adrenocortical carcinomas: surgical trends and re- sults of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001;25:891-7.
[5] Schulick RD, Brennan MF. Long-term survival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol 1999;6:719-26.
[6] Venkatesh S, Hickey RC, Sellin RV, et al. Adrenal cortical carcinoma. Cancer 1989;64:765-9.
[7] Wajchenberg BL, Albergaria Pereira MA, Medonca BB, et al. Adrenocortical carcinoma: clinical and laboratory observations. Cancer 2000;88:711-36.
[8] Hsing AW, Nam JM, Co Chien HT, et al. Risk factors for adrenal cancer: an exploratory study. Int J Cancer 1996;65:432-6.
[9] van Seters AP, van Aalderen W, Moolenaar AJ, et al. Adrenocortical tumour in untreated congenital adrenocortical hyperplasia associated with inadequate ACTH suppressibility. Clin Endocrinol (Oxf) 1981;14:325-34.
[10] Pang S, Becker D, Cotelingam J, et al. Adrenocortical tumor in a patient with congenital ad- renal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 1981;68:242-6.
[11] Wu SD. Carcinoma of Adrenal Cortex. Chin Med J (Engl) 1940;(Suppl 3):52-93.
[12] Macfarlane DA. Cancer of the adrenal cortex; the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl 1958;23:155-86.
[13] Latronico AC, Chrousos GP. Extensive personal experience: adrenocortical tumors. J Clin Endocrinol Metab 1997;82:1317-24.
[14] Dunton RF, Deckers PJ. Estrogen producing adrenocortical carcinoma in an adult male. Contemp Surg 1987;30:63-7.
[15] Allolio B, Hahner S, Weismann D, et al. Management of adrenocortical carcinoma. Clin En- docrinol (Oxf) 2004;60:273-87.
[16] Kendrick ML, Curlee K, Lloyd R, et al. Aldosterone-secreting adrenocortical carcinomas are associated with unique operative risks and outcomes. Surgery 2002;132:1008-11.
[17] Stewart PM, Walker BR, Holder G, et al. 11 beta-Hydroxysteroid dehydrogenase activity in Cushing’s syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocor- ticotropin syndrome. J Clin Endocrinol Metab 1995;80:3617-20.
[18] Ribeiro RC, Sandrini Neto RS, Schell MJ, et al. Adrenocortical carcinoma in children: a study of 40 cases. J Clin Oncol 1990;8:67-74.
[19] Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognos- tic factors, and the effect of mitotane therapy. N Engl J Med 1990;322:1195-201.
[20] Hutter AM Jr, Kayhoe DE. Adrenal cortical carcinoma. Results of treatment with o,p’DDD in 138 patients. Am J Med 1966;41:581-92.
[21] Icard P, Chapuis Y, Andreassian B, et al. Adrenocortical carcinoma in surgically treated pa- tients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 1992;112:972-9.
[22] Humphrey GB, Pysher T, Holcombe J, et al. Overview on the management of adrenocortical Carcinoma (ACC). Cancer Treat Res 1983;17:349-58.
[23] Barnett CC Jr, Varma DG, El-Naggar AK, et al. Limitations of size as a criterion in the eval- uation of adrenal tumors. Surgery 2000;128:973-82.
[24] Koch CA, Pacak K, Chrousos GP. The molecular pathogenesis of hereditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 2002;87:5367-84.
[25] Beuschlein F, Reincke M, Karl M, et al. Clonal composition of human adrenocortical neo- plasms. Cancer Res 1994;54:4927-32.
[26] Sameshima Y, Tsunematsu Y, Watanabe S, et al. Detection of novel germ-line p53 mutations in diverse-cancer-prone families identified by selecting patients with childhood adrenocorti- cal carcinoma. J Natl Cancer Inst 1992;84:703-7.
[27] Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250:1233-8.
[28] Reincke M, Karl M, Travis WH, et al. p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 1994;78:790-4.
[29] Wagner J, Portwine C, Rabin K, et al. High frequency of germline p53 mutations in child- hood adrenocortical cancer. J Natl Cancer Inst 1994;86:1707-10.
[30] Gicquel C, Bertagna X, Schneid H, et al. Rearrangements at the 11p15 locus and overexpres- sion of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J Clin Endocri- nol Metab 1994;78:1444-53.
[31] Weber MM, Fottner C, Wolf E. The role of the insulin-like growth factor system in adreno- cortical tumourigenesis. Eur J Clin Invest 2000;30(Suppl 3):69-75.
[32] Ilvesmaki V, Kahri AI, Miettinen PJ, et al. Insulin-like growth factors (IGFs) and their re- ceptors in adrenal tumors: high IGF-II expression in functional adrenocortical carcinomas. J Clin Endocrinol Metab 1993;77:852-8.
[33] Zwermann O, Schulte DM, Reincke M, et al. ACTH 1-24 inhibits proliferation of adreno- cortical tumors in vivo. Eur J Endocrinol 2005;153:435-44.
[34] Reincke M, Mora P, Beuschlein F, et al. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis. J Clin Endocrinol Metab 1997;82:3054-8.
[35] Skogseid B, Larsson C, Lindgren PG, et al. Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 1992;75:76-81.
[36] Schussheim DH, Skarulis MC, Agarwal SK, et al. Multiple endocrine neoplasia type 1: new clinical and basic findings. Trends Endocrinol Metab 2001;12:173-8.
[37] Langer P, Cupisti K, Bartsch DK, et al. Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg 2002;26:891-6.
[38] Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427-34.
[39] Nwariaku FE, Champine J, Kim LT, et al. Radiologic characterization of adrenal masses: the role of computed tomography-derived attenuation values. Surgery 2001;130:1068-71.
[40] Peppercorn PD, Reznek RH. State-of-the-art CT and MRI of the adrenal gland. Eur Radiol 1997;7:822-36.
[41] Copeland PM. The incidentally discovered adrenal mass. Ann Intern Med 1983;98:940-5.
[42] Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 2003;138:424-9.
[43] Dackiw AP, Lee JE, Gagel RF, et al. Adrenal cortical carcinoma. World J Surg 2001;25: 914-26.
[44] Sullivan M, Boileau M, Hodges CV. Adrenal cortical carcinoma. J Urol 1978;120:660-5.
[45] Lee JE, Berger DH, el-Naggar AK, et al. Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 1995;118:1090-8.
[46] Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adreno- cortical tumors. Am J Surg Pathol 1984;8:163-9.
[47] Hough AJ, Hollifield JW, Page DL, et al. Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data. Am J Clin Pathol 1979;72: 390-9.
[48] van Slooten H, Schaberg A, Smeenk D, et al. Morphologic characteristics of benign and ma- lignant adrenocortical tumors. Cancer 1985;55:766-73.
[49] Wachenfeld C, Beuschlein F, Zwermann O, et al. Discerning malignancy in adrenocortical tumors: are molecular markers useful? Eur J Endocrinol 2001;145:335-41.
[50] Schröder S, Niendorf A, Achilles E, et al. Immunocytochemical differential diagnosis of adrenocortical neoplasms using the monoclonal antibody D11. Virchows Arch A Pathol Anat Histopathol 1990;417:89-96.
[51] Tartour E, Caillou B, Tenenbaum F, et al. Immunohistochemical study of adrenocortical carcinoma. Predictive value of the D11 monoclonal antibody. Cancer 1993;72:3296-303.
[52] Velazquez-Fernandez D, Laurell C, Geli J, et al. Expression profiling of adrenocortical neo- plasms suggests a molecular signature of malignancy. Surgery 2005;138:1087-94.
[53] Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mi- totane and a review of the literature. Cancer 1993;72:3145-55.
[54] Chiche L, Dousset B, Kieffer E, et al. Adrenocortical carcinoma extending into the inferior vena cava: presentation of a 15-patient series and review of the literature. Surgery 2006;139: 15-27.
[55] Gonzalez RJ, Shapiro S, Sarlis N, et al. Laparoscopic resection of adrenal cortical carci- noma: a cautionary note. Surgery 2005;138:1078-85.
[56] Wood BJ, Abraham J, Hvizda JL, et al. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 2003;97:554-60.
[57] Bergenstal D, Hertz R, Lipsett MB, et al. Chemotherapy of adrenocortical cancer with O,P’-DDD. Ann Intern Med 1960;53:672-82.
[58] Lubitz JA, Freeman L, Okun R. Mitotane use in inoperable adrenal cortical carcinoma. JAMA 1973;223:1109-12.
[59] Henley DJ, van Heerden JA, Grant CS, et al. Adrenal cortical carcinoma-a continuing chal- lenge. Surgery 1983;94:926-31.
[60] Karakousis CP, Rao U, Moore R. Adrenal adenocarcinomas: histologic grading and sur- vival. J Surg Oncol 1985;29:105-11.
[61] Haak HR, Hermans J, van de Velde CJ, et al. Optimal treatment of adrenocortical carci- noma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994;69: 947-51.
[62] van Slooten H, Moolenaar AJ, van Seters AP, et al. The treatment of adrenocortical carci- noma with o,p’-DDD: prognostic implications of serum level monitoring. Eur J Cancer Clin Oncol 1984;20:47-53.
[63] Markoe AM, Serber W, Micaily B, et al. Radiation therapy for adjunctive treatment of ad- renal cortical carcinoma. Am J Clin Oncol 1991;14:170-4.
[64] Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 1993;71:3119-23.
[65] Bodie B, Novick AC, Pontes JE, et al. The Cleveland Clinic experience with adrenal cortical carcinoma. J Urol 1989;141:257-60.
[66] Baudin E, Pellegriti G, Bonnay M, et al. Impact of monitoring plasma 1,1-dichlorodiphenil- dichloroethane (o,p’DDD) levels on the treatment of patients with adrenocortical carci- noma. Cancer 2001;92:1385-92.
[67] Haq MM, Legha SS, Samaan NA, et al. Cytotoxic chemotherapy in adrenal cortical carci- noma. Cancer Treat Rep 1980;64:909-13.
[68] Decker RA, Elson P, Hogan TF, et al. Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 1991;110:1006-13.
[69] Flynn SD, Murren JR, Kirby WM, et al. P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma. Surgery 1992;112:981-6.
[70] Haak HR, van Seters AP, Moolenaar AJ, et al. Expression of P-glycoprotein in relation to clinical manifestation, treatment and prognosis of adrenocortical cancer. Eur J Cancer 1993; 29A:1036-8.
[71] Bates SE, Shieh CY, Mickley LA, et al. Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also ex- pressed by adrenocortical carcinomas. J Clin Endocrinol Metab 1991;73:18-29.
[72] Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. En- docr Relat Cancer 2005;12:657-66.
[73] Allolio B, Jaursch-Hancke C, Reincke M, et al. [Treatment of metastatic adrenal carcinoma with suramin]. Dtsch Med Wochenschr 1989;114:381-4 [in German].
[74] Miglietta L, Barreca A, Repetto L, et al. Suramin and serum insulin-like growth factor levels in metastatic cancer patients. Anticancer Res 1993;13:2473-6.
[75] Arlt W, Reincke M, Siekmann L, et al. Suramin in adrenocortical cancer: limited efficacy and serious toxicity. Clin Endocrinol (Oxf) 1994;41:299-307.
[76] Wu YW, Chik CL, Knazek RA. An in vitro and in vivo study of antitumor effects of gossypol on human SW-13 adrenocortical carcinoma. Cancer Res 1989;49:3754-8.
[77] Flack MR, Pyle RG, Mullen NM, et al. Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab 1993;76:1019-24.
[78] Allolio B, Schulte HM, Kaulen D, et al. Nonhypnotic low-dose etomidate for rapid correc- tion of hypercortisolaemia in Cushing’s syndrome. Klin Wochenschr 1988;66:361-4.
[79] Thoren M, Adamson U, Sjoberg HE. Aminoglutethimide and metyrapone in the manage- ment of Cushing’s syndrome. Acta Endocrinol (Copenh) 1985;109:451-7.
[80] Verhelst JA, Trainer PJ, Howlett TA, et al. Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing’s syndrome. Clin Endocrinol (Oxf) 1991;35:169-78.
[81] Contreras P, Rojas A, Biagini L, et al. Regression of metastatic adrenal carcinoma during palliative ketoconazole treatment. Lancet 1985;2:151-2.
[82] Sinnaeve LJ, Becks GP. Preoperative ketoconazole therapy for adrenocortical carcinoma. CMAJ 1989;141:131-3.
[83] Sonino N, Boscaro M, Paoletta A, et al. Ketoconazole treatment in Cushing’s syndrome: experience in 34 patients. Clin Endocrinol (Oxf) 1991;35:347-52.
[84] Engelhardt D, Jacob K, Doerr HG. Different therapeutic efficacy of ketoconazole in patients with Cushing’s syndrome. Klin Wochenschr 1989;67:241-7.
[85] Engelhardt D, Weber MM. Therapy of Cushing’s syndrome with steroid biosynthesis inhib- itors. J Steroid Biochem Mol Biol 1994;49:261-7.