Androgen- and Estrogen-Secreting Adrenal Cancers
Dominic Cavlan,ª Nishat Bharwani,b and Ashley Grossman“
Androgen-secreting adrenal cancers are extremely rare malignancies, accounting for only a tiny proportion of the total number of women presenting with signs of androgen excess. Estrogen- secreting adrenal cancers are rarer still. Understanding how these tumors work benefits from an appreciation of adrenal steroid biosynthesis, as it is said that secretion in cancers is an anarchic version of normal adrenal function. Selection of patients in whom we should have a high suspicion of a malignancy is vital, so that biochemical investigation and imaging is deployed appropriately. When an adrenal tumor is found to secrete androgens or estrogens to excess, it can be difficult to confirm that it is a cancer, as there is significant overlap in the secretory patterns and imaging appearances of benign and malignant disease. The most reliable indicator of malignancy in these tumors remains the presence of metastases. Treatment is essentially surgical, although the role of mitotane is one undergoing evaluation.
Semin Oncol 37:638-648 @ 2010 Elsevier Inc. All rights reserved.
B enign and malignant tumors of the adrenal gland may be nonfunctioning or hypersecretory. When they are functioning they tend to secrete cortisol or aldosterone, but in rare cases they may secrete androgens, and in very rare cases estrogens. Malignant tumors of the adrenal gland secreting andro- gens and estrogens are the subject of this review. We will consider the physiology of androgen and estrogen secretion from the normal adrenal gland, and the clin- ical presentation when secretion is in excess. Female patients presenting with hirsutism or virilisation are much more likely to have polycystic ovarian syndrome than an androgen-secreting adrenal cancer; we will discuss how to identify those who do in a cost-effective manner. We will explore how these tumors are imaged and staged, noting that it can be difficult to determine whether androgen- and estrogen-secreting adrenal can- cers are malignant according to the standard criteria used in adrenocortical carcinoma. We will finally con-
aDepartment of Endocrinology, Barts and The London NHS Trust, Lon- don, UK.
bDepartment of Radiology, Royal Free Hampstead, London, UK.
“Department of Endocrinology, Centre for Endocrinology, Barts and the London School of Medicine, London, UK.
Financial disclosure obligations: none.
Address correspondence to Ashley Grossman, MD, Department of En- docrinology, St. Bartholomew’s Hospital, London EC1A 7BE, UK. E-mail: A.B.Grossman@qmul.ac.uk
0270-9295/ - see front matter
@ 2010 Elsevier Inc. All rights reserved.
doi:10.1053/j.seminoncol.2010.10.016
sider current treatments used to manage these rare malignancies.
ADRENAL ANDROGEN PHYSIOLOGY
The adrenal gland produces androgens from the zona reticularis and in smaller amounts from the zona fasciculata. The pathway for steroidogenesis is illus- trated in Figure 1. The major androgens secreted are dihydroepiandrosterone (DHEA) and its sulfate (DHEAS), and androstenedione (A4). There is only a small amount of directly synthesized testosterone. These “adrenal an- drogens” have only weak androgenic activity, but when secreted in excess from an androgen producing adrenal cancer can produce a marked clinical phenotype. Se- cretion is largely under the control of corticotrophin (ACTH), and follows the same diurnal rhythm as corti- sol, but a number of other endocrine signals have been posited as regulators, including prolactin, the gonado- trophins, and estrogens.1
The secretion of adrenal androgens gradually in- creases with age as the zona reticularis develops, and it is the rise in adrenal androgens at adrenarche that stimulates the appearance of pubic hair. Cortisol secre- tion at this time remains constant, again suggesting that androgen secretion may be outside of ACTH control alone. Gell et al2 proposed that it is a decrease in levels of 3ß-hydroxysteroid dehydrogenase in the zona reticu- laris at this time, guiding the steroid precursors down the pathway leading to DHEA and DHEAS production.
DHEA, DHEAS, and A4 are converted to the more potent androgens testosterone and dihydrotestoster-
Cholesterol
Pregnenolone
36-HSD
Progesterone
21
Deoxy- corticosterone
116
Corticosterone
18
Aldosterone
17a
17a
17OH- Pregnenolone
36-HSD
17-OH Progesterone
21
11-deoxycortisol
116
Cortisol
17,20
17,20
17,20
176-HSD
DHEA
36-HSD
Androstenedione
Testosterone
5a red.
Dihydro- testosterone
Sulfotransferase
AROMATASE
AROMATASE
DHEA-S
Estrone
176-HSD
Estradiol
one (DHT) in peripheral tissues, in particular the hair follicles, external genitalia, and sebaceous glands. In women, 25% of circulating testosterone comes direct from the adrenal, 50% from peripheral conversion of adrenal androgens, and 25% from the ovary. DHEA and DHEAS are the most abundant steroids in the human circulation.3
In premenopausal women, the ovaries are the prin- cipal source of estradiol, but in men and postmeno- pausal women this is not the case. Estrogen production from adrenal androgens occurs in a number of periph- eral sites (adipose tissue, osteoblasts and chondrocytes of bone, vascular epithelium), and requires the en- zymes 17ß-hydroxysteroid dehydrogenase and aro- matase, as shown in Figure 1. Small quantities of estro- gen are produced directly by the adrenal glands, with levels of aromatase tending to be low.4 As we shall see, estrogen-producing adrenal cancers are extremely rare, and may be associated with an increase in aromatase expression in this tissue.
Excessive adrenal androgen production in the adult male does not seem to have any major clinical conse- quences, while in pre-pubertal boys it can present as isosexual precocious puberty. The more marked clini- cal consequences are seen in females, where adrenal androgens make a more substantial contribution to total androgen levels. The adult female may present with symptoms of hirsutism, virilization, or menstrual irregularity. Hirsutism is defined as excessive terminal hair that appears in a male pattern.5 Virilization in- cludes clitoromegaly, male pattern hair loss, deepening of the voice, increased muscle strength, and cystic acne. Pre-pubertal girls with hyperandrogenism may present with heterosexual precocious puberty. This presentation is usually benign, but patients presenting with signs of estrogen excess- gynecomastia and hy-
pogonadism in men-are much more likely to have an estrogen-secreting tumor.
ADRENOCORTICAL CARCINOMA
Adrenocortical carcinoma (ACC) is a rare disease, accounting for 0.05% to 2% of all cancers.6,7 It has an estimated incidence of 1-2 per million population per year, with women affected more often than men in most published series.8-10 The prognosis is poor, with 5-year survival rates in adults of approximately 30%. Some 30% to 50% present with advanced stage IV disease, in which case the 5-year survival is less than 5%. A bimodal distribution has been reported with peaks in the first and fourth decades.8,11,12 In children, the incidence is considered as 10 times lower except in South Brazil where there is a higher incidence of pedi- atric ACC, explained by an inherited p53 germline mutation. 13
A diagnosis of ACC might be suspected on the basis of clinical signs of hormone excess, or by effects of the tumor mass or its metastases. The majority (~60%) of ACCs are secreting tumors when the appropriate bio- chemical tests are performed.14,15 The European Net- work for the Study of Adrenal Tumours (ENSAT) recom- mends an appropriate work-up as outlined in Table 1.15
Most patients presenting with an ACC do so with signs and symptoms of adrenal steroid excess, but these may not be obvious. This is most frequently rapidly pro- gressive Cushing’s syndrome (30%-40%). While benign adrenocortical tumors tend to secrete a single class of steroid, ACC can secrete various types, and co-secretion of cortisol with androgens is a frequent combination, and highly suggestive of malignancy.8,10,13,16 These co-secret- ing tumors seem to be more common in women. When Moreno et al looked at 65 female patients following
| Table1. Recommended Diagnostic Work-up in Patients With Suspected or Proven Adrenocortical Car- cinoma (ENSAT, May 2005) | |
|---|---|
| Endocrine Investigations | |
| Glucocorticoid excess (minimum 3 of 4 tests) | Dexamethasone suppression test |
| Excretion of free urinary cortisol (24-h urine) | |
| Basal cortisol (serum) | |
| Basal ACTH (serum) | |
| Sexual steroids and precursors | DHEAS |
| 17-OH progesterone | |
| Androstenedione | |
| Testosterone | |
| 17ß-estradiol (men and postmenopausal women) | |
| Mineralocorticoid excess | Potassium (serum) |
| Aldosterone/renin ratio (in patients with hypertension or hypokalemia) | |
| Exclusion of pheochromocytoma (minimum 1 of 3 tests) | 24-h urine catecholamines |
| 24-h urine metanephrines | |
| Meta- and normetanephrines (plasma) | |
| Imaging | CT or MRI of abdomen and CT of thorax Bone scintigraphy (if bone metastases is suspected) FDG-PET (optional) |
adrenalectomy for Cushing’s syndrome, they found that 22 had virilization: of the virilized patients, 65% had malignant disease.17 In all series of patients with androgen-secreting tumors, there is a female predomi- nance, with males accounting for 10% to 35% of the reported cases, but the signs of hyperandrogenism are of course more apparent in females.13,18
Abiven et al14 found 76% of their series of 202 consecutive adult patients with ACC to be secretory. Of those, the majority (46%) secreted both cortisol and androgens, 27% cortisol alone, and only 6% were pure androgen-secreting adrenal tumors (PASATs). Aldoste- rone-secreting ACCs are extremely rare but can present with hypokalemia and hypertension. Estrogen-secret- ing ACCs are rarer still, and felt to be invariably malig- nant.
When ACC presents in children, it tends to do so with virilization, and to run a less aggressive course.11 Almost all ACCs in children are functional, and these present predominantly as PASATs (40%-60%).15 Chil- dren whose disease is localized, and completely re- sected, and whose hormonal profile is normal after surgery, have a 90% long-term survival rate.19
PURE ANDROGEN- SECRETING ADRENAL TUMORS
The publication of two recent series of PASATs17,20 has added to our understanding of these rare tumors. Cordera et al20 identified 11 patients, all female, from those presenting with androgen excess and an adrenal tumor from 1946 to 2002. Moreno et al looked exclu-
sively at female patients and found 21 having adrenal- ectomy for PASATs from 1970 to 2003.17 In both groups approximately 50% of the tumors were malig- nant.
The Cordera group noted that factors associated with a poor prognosis in PASATs were incomplete resection, mass >100 g, volume >100 ml, age >3.5 years at diagnosis, or more than 6 months of symptoms prior to diagnosis. However, the prognosis was still better than ACCs in general, with only one of the four patients with a malignant PASAT dying from their dis- ease, and this in a patient with metastases at presenta- tion.
Neither group was able to define a qualitative secre- tory profile that was even suggestive of malignancy, let alone diagnostic. However, a highly elevated testoster- one level (>7.40 ng/ml or >11 times normal) sug- gested a malignant pathology.
The molecular basis for androgen secretion from malignant adrenal tumors has been described as “anar- chic”-not fundamentally different from normal, sim- ply quantitatively increased.21 Sciarra reports the over- expression of a cytochrome b6 in some virilizing ACCs,22 and speculated that a downstream activation of 17,20 lyase may be responsible for the excess androgen secretion.
Imai et al21 looked at in vitro steroidogenesis in virilizing adrenocortical adenomas and found that stim- ulation with ACTH did not increase the level of se- creted androgens, as it would in normal adrenal tissue. In addition, dexamethasone suppression did not de-
crease the level of androgens; this distinction has proven to be useful clinically in distinguishing between neoplastic and non-neoplastic causes of hirsutism. ACTH-receptor mRNA was absent from the virilizing tumor tissue, suggesting that a lack of ACTH-receptor expression may be responsible for these findings.
An elevated serum testosterone level in ACC is usu- ally a consequence of peripheral conversion of adrenal androgens. Tumors that secrete purely testosterone are described but are extremely rare. Mattox and Phelan23 found only 47 in the literature between 1925 and 1987.
ESTROGEN-SECRETING ADRENAL CANCERS
Estrogen-secreting adrenal tumors can present in females with precocious puberty or postmenopausal bleeding. In the male they can present with feminiza- tion: gynecomastia, testicular atrophy, and/or dimin- ished libido. Gynecomastia is the most common pre- senting complaint, with hypogonadism likely due to the suppression of gonadotrophins by the excess estro- gens. Hypertension is occasionally present in feminiz- ing adrenal tumors as a result of mineralocorticoid secretion24,25 but possibly aided by hepatic stimulation of renin precursors by the elevated estrogens.26 Most feminizing adrenal tumors occur in males aged 24 to 45 years,27,28 but they have been reported in females, and before puberty in both sexes.29,30
Bittorf was the first to describe feminization in a male from an adrenocortical tumor in 191931 in a 26- year-old male who presented with gynecomastia. Fem- inization in the context of an adrenal tumor is consid- ered almost pathognomonic of malignancy.32 Moreno et al33 estimated that 1% to 2% of all ACCs are feminiz- ing. They tend to be larger, and the prognosis is much worse than for other varieties of ACC, either secretory or nonsecretory. Gabrilove et al34 reported a 20% 3-year survival in 1965, although Bhettay and Bonnici35 sug- gested that the prognosis in children might be more optimistic.
Elevated estrogen levels in some feminizing tumors are a result of extraglandular aromatization of steroid precursors. Elevated levels of estrone and estradiol have been found in virilizing tumors by the same mech- anism. Direct secretion of estrogens by ACCs requires expression of the enzymes aromatase and 17ß-hydrox- ysteroid dehydrogenase. Zayed et al36 estimated that, in one woman with ACC and high serum androgens and estrone, half of the circulating estrone had come di- rectly from the tumor and half from peripheral conver- sion of androstenedione.
Both Kimura et al37 and Young et al38 have reported increased aromatase activity in comparison with nor- mal adrenal gland and adipose tissue in patients with feminizing ACC. Goto et al39 reported a 65-year-old woman presenting with abnormal vaginal bleeding and a right-sided adrenal mass on computed tomography
(CT). In this patient adrenal venous sampling demon- strated excessive estrogen secretion from the tumor, and histopathology revealed an adenoma with aro- matase activity equivalent to a full-term human pla- centa. However, Bouraïma et al40 found that in the excised ACC of a 30-year-old man presenting with rapid gynecomastia, there was only a moderate increase in aromatase activity in the tumor in comparison with non-neoplastic adrenal tissue. There was no significant difference in expression of aromatase mRNA between tumor and normal adrenal tissue, suggesting some translational modification of the aromatase protein, or an increase in its half-life. Nicol et al41 were able to demonstrate this translational control in a cell line derived from human ACC cells (NCI-H295).
Watanabe et al,29 on the other hand, in their discus- sion of an 18-month-old boy with an estrogen-secreting ACC, suggested that the increase in aromatase expres- sion might be due to a change in the exon used to the gonadal type (1c to 1b). A similar shift in expression occurs in breast cancer cells under the influence of certain associated cytokines.
As well as aromatase, the secretion of estrogens by feminizing adrenal tumors requires one or more of the 17ß-hydroxysteroid dehydrogenases (17-ketosteroid re- ductases). Nicol et al41 were also able to demonstrate the constitutive expression of AKR1C3-type 5 17B- hydroxysteroid dehydrogenase-in the NCI-H295 cell line. They also showed that the expression of AKR1C3 was higher in a feminizing ACC than in an aldosterone- secreting adrenal adenoma by Western immunoblot- ting, and that CYP19 (aromatase) expression was present in the former, and absent in the latter.
Recently, Shen et al42 looked at estrogen receptor (ER) expression in ACC. In a small study of 17 cases of ACC they found that ER positivity was correlated with a better prognosis, and suggested the putative role of estrogen as a growth-modulating factor to account for this.
CLINICAL EVALUATION OF THE PATIENT WITH HIRSUTISM OR VIRILIZATION
Most diagnoses of androgen-secreting adrenal can- cers are made in women presenting with hirsutism or virilization, but they make up only a very small percent- age of this population. Among reproductive aged women in the general population, it is estimated that 5% are hirsute, and 7% have biochemical androgen excess.5 In contrast, only 0.2% of cases of hyperandro- genism are a result of androgen-secreting adrenal tu- mors, and only half of these are malignant.43 Ovarian tumors comprise a similar proportion, and include ar- rhenoblastoma (Sertoli-Leydig cell tumor) and theca cell tumors. Polycystic ovarian syndrome (PCOS) is the cause of hyperandrogenism in 95% of cases.44
Distinguishing the two conditions solely on clinical
Signs of Hyperandrogenism
Biochemical Evaluation Testosterone DHEAS Androstenedione 17-OH Progesterone Cortisol LH & FSH IGF-1 (if clinically indicated)
Elevation of Testosterone
LDDST
Failure of testosterone suppression
CT Adrenals Ultrasound Ovaries
Consider reverse circadian prednisolone if initial imaging does not reveal a tumour
grounds requires caution. Some authors have regarded severe or rapidly progressive virilization as the only feature that merits further evaluation.45 While this should arouse suspicion, particularly in older women, it neglects the slowly evolving virilizing adrenal tumors that can present in an identical manner to PCOS (in- cluding with raised luteinizing hormone levels). Find- ing acanthosis nigricans or being reassured by the ap-
(a)
(b)
(c)
pearance of polycystic ovaries on ultrasound44 is hazardous, and has been associated with delayed diag- nosis in patients with ACC.46 One also must be aware that the clinical phenotype of PCOS can be associated with other endocrine disease, including Cushing’s syn- drome, acromegaly, and late-onset congenital adrenal hyperplasia.
The Endocrine Society guidelines for the assessment of hirsutism caution against testing for elevated andro- gen levels in patients with only isolated mild hirsutism, as the likelihood of identifying a medical disorder that would change management is low.47 They recommend testing in patients with moderate to severe hirsutism, or when it is rapidly progressing or associated with irregular menses, clitoromegaly, or central obesity- suggesting excess cortisol.
By contrast, some investigators have felt that the clinical examination plus a basal testosterone level is adequate for screening,23,48 but a single elevated level has a low positive predictive value for identifying vir- ilizing tumors.49 In one series of androgen-secreting tumors, while a testosterone value greater than 7.3 nmol/L was only found in patients with virilizing tu- mors, over half of patients with tumors had testoster- one levels within the range observed in patients with non-tumoral hyperandrogenism.46 When the androgen profiles of androgen-secreting adrenal tumors have been compared with hyperandrogenism from other causes, half of the tumors have had one or two andro- gens in the normal range.50
The testosterone response during a 48-hour low- dose (2 mg) dexamethasone suppression test (LDDST) can be used to distinguish virilizing adrenal tumors and ovarian tumors from other causes of hyperandro- genism.5,46,51-53 Derksen et al found that administration of dexamethasone 3 mg/d for 5 days had a sensitivity
and specificity of 100% for identifying patients with androgen-secreting adrenal tumors,53 while Kaltsas et al demonstrated a sensitivity of 100% and specificity of 88% for distinguishing PCOS from adrenal and ovarian tumours using the LDDST.46 Our departmental proto- col for the investigation of women with symptoms of hyperandrogenism uses the LDDST, and is illustrated in Figure 2.
If biochemical and imaging data fail to confirm the presence of a suspected androgen-secreting tumor, ad- renal venous sampling may be useful as a last resort, but it is highly operator-dependent, and a recent series from our unit showed that it rarely provided useful additional information.54
IDENTIFYING MALIGNANT TUMORS
When an androgen- or estrogen-secreting adrenal tumor has been identified, discerning whether it is benign or malignant is not straightforward. One may consider the pattern of hormone secretion or the spe- cifics of the clinical presentation, the characteristics on imaging, or the pathological specimen after adrenalec- tomy. With each of these there is marked overlap between benign and malignant disease. The only defin- itive criterion to indicate malignancy is the presence of metastatic disease.55
As we have noted, feminizing adrenocortical tumors are almost invariably malignant although benign adeno- mas are reported.35,56 Elevated DHEAS levels have been proposed as an indicator of malignancy in androgen- secreting adrenal tumors, as high levels are found in a significant proportion of ACCs.6,57 However, there is a wide variation between individuals, and in one series half of the patients with ACC presenting as incidenta- loma had a low DHEAS.32,58,59 In their PASAT series,
(a)
(b)
Moreno et al reported that highly elevated levels of testosterone at 11 times normal should suggest a ma- lignant pathology.17 One difficulty with using any of the secreted androgens to predict malignancy is that these may change in tandem with the size, growth rate, and differentiation of the tumor.12
Cross-sectional imaging can readily characterize be- nign adrenal masses such as lipid-rich adenomas or myelolipomas, but lipid-poor adenomas and ACCs are more likely to remain indeterminate.60 An attenuation value of less than 10 Hounsfield units on unenhanced computerised tomography (CT) is a widely used thresh- old for diagnosing an adrenal lesion as a benign adeno- ma,61 but 30% of adenomas are lipid-poor and may share attenuation characteristics with ACC. When an unenhanced CT is not available or an adrenal lesion has an attenuation of greater than 10 Hounsfield units, delayed contrast-enhanced CT (CECT) can be per- formed to calculate the absolute or relative washout characteristics of a lesion.62-64 ACCs retain intravenous contrast and have absolute and relative percentage washout of <60% and <40%, respectively, at 15 min- utes.62,64 An example of the use of CT washout in a patient with a virilizing tumor is shown in Figure 3.
Lesion size (>4 cm) and the presence of heteroge- neous enhancement have been shown to be the most important discriminators of malignancy, but malignant tumors <3 cm, and benign lesions >5 cm diameter, are well described.65-67 Calcification is seen in approxi- mately 30% of ACCs and is usually centrally located, as shown in Figure 4.55
ACCs are typically heterogeneous in signal intensity on magnetic resonance imaging (MRI) (Figure 5). Hy- perintensity on T2-weighted imaging is a reflection of intratumoral cystic regions and hemorrhage (cf, non- functioning adenomas, which tend to have a lower T2-weighted signal intensity), but still 31% of lesions remain indeterminate.68,69 Enhancement with gadolin- ium is more likely to be heterogeneous in ACC and homogeneous or ring enhancing in adenomas, but again there is considerable overlap. Chemical-shift imag- ing (CSI) is an MRI technique that uses certain character- istics of water and fat molecules in a magnetic field to differentiate adrenal lesions based on their lipid content, adding this feature to standard and gadolinium-enhanced MRI has been reported to distinguish adenomas from non-adenomas with an accuracy of 90%.70,71 Benign ade- nomas show uniform signal loss, while malignant le- sions show <30% signal loss on out-of-phase imaging.62
18F-fluorodeoxyglucose positron emission tomogra- phy (FDG-PET) scanning can recognize some malignant adrenal masses by virtue of their increased metabolic activity, but when there is only modest FDG uptake the likelihood of benign versus malignant is about equal.72 Combined FDG-PET data with contrast-enhanced CT scanning has a sensitivity of 100% and specificity of 98% for identifying malignant adrenal masses. PET
specificity can be improved by using [11C]-metomidate, a marker of 11ß-hydroxylase, as a tracer for adrenocor- tical tissue, but the most valuable aspect of PET scan- ning is its ability to detect metastases elsewhere in the body. Images from combined FDG-PET CT demonstrat- ing metastases are shown in Figure 6. It is worth em- phasizing again that one third of patients with ACC will have metastatic disease at presentation.32 Percutaneous biopsies of androgen- or estrogen-secreting adrenal tu- mors are not justified in the light of risks of inducing tumor capsule breakdown and tumor spread.
From a histopathological perspective, there is a marked overlap between adrenal tumors that are be- nign and those secreting androgens and estrogens. The most widely used scoring system to assess the patho- logical specimen is the Weiss system, which combines nine different parameters, each scoring a single point73: three are structural, three cytological, and three are related to invasion. A score of 3 or more is consistent with a malignant tumor with sensitivity 100% and spec- ificity 96%, but ACCs have been found with a Weiss
a
b
(C)
0
0
D
(a)
0
(b)
(c)
score of 2 and there have been androgen-secreting adrenal tumors reported with a Weiss score of 4 that showed no recurrence (these tended to be PASATs). In feminizing tumors, the clinicoradiological assessment is felt to be more useful than the histopathological assess- ment,30 and some investigators insist that malignancy is only revealed by the presence of metastases.74 In the pediatric population it is still more difficult to define malignancy, as not all the parameters used in the Weiss system are markers of malignancy in this group.75 Among genetic and molecular markers the presence of insulin-like growth factor-2 (IGF-2) and glucose trans- porter-1 (GLUT-1) over-expression in ACCs look to be the most promising as diagnostic and prognostic tools in future, and it is suggested that they will prove more important than either imaging or histopathology.76
TREATMENT OF ANDROGEN- AND ESTROGEN-PRODUCING ADRENAL CANCERS
ACC is such a rare disease that a strong evidence base for its treatment is lacking, but the mainstay of therapy is surgical excision of the primary tumor, with a low threshold for en bloc resection of adjacent vis- cera. Even following a complete resection the recur- rence rate is 60% to 80%.77,78 The expertise of the surgeon is held to be more important than the specific
surgical technique. Radiotherapy is appropriate in pa- tients at high risk for local recurrence, as defined by an incomplete or indeterminate resection, or advanced locoregional disease, or “aggressive” levels of Ki-67-a marker of cellular proliferation-above 20%. It should be started within 3 months. Medical therapy is primarily with mitotane (O’,p’DDD), with a role in both adjuvant treatment and advanced disease. Approximately 20% to 25% of ACCs respond to mitotane,79 and in these patients adjuvant mitotane therapy has the potential to prolong both disease-free and overall survival.80
Repeat surgery should be considered if there is dis- ease recurrence after surgery, and here mitotane is certainly indicated. In metastatic disease mitotane is the primary option, while the first ever phase III trial looking at cytotoxic chemotherapy in these patients is ongoing.81 The use of erlotinib, gefitinib, and bevaci- zumab may have a future role, and trials are ongoing currently. As for ACC in general, a role for chemother- apy is highly controversial.
CONCLUSIONS
Androgen- and estrogen-secreting adrenal cancers are rare malignancies with a poor prognosis, and it is therefore vitally important that they are identified promptly in patients presenting with signs of hormone
excess. This is not straightforward, as there is signifi- cant overlap between benign and malignant disease in terms of the clinical manifestations, the hormonal pro- file, and the radiological and pathological appearances. However, it is rare to diagnose such tumors in the absence of floridly abnormal adrenal imaging. The pres- ence of metastases is the most reliable indicator of malignancy. Other than mitotane we are still sadly lacking in effective therapies, but it is hoped that novel treatments based on molecular targeting will change the current gloomy outlook.
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