HORMONE RESEARCH
Horm Res 2009;71(suppl 1):99-104 DOI: 10.1159/000178049
Adrenocortical Cancer Treatment
A. Patalano V. Brancato F. Mantero
Unit of Endocrinology, Department of Medical and Surgical Sciences, University of Padua, Padua, Italy
Key Words
Adrenocortical cancer . Mitotane · FIRM-ACT
Abstract
Background: With a reported incidence of 1 to 2 cases per million, adrenocortical cancer (ACC) is a rare disease with poor prognosis. Age distribution shows two peaks: early childhood and between age 40 and 50 years, with females more frequently affected. Sequelae can include Cushing syndrome, virilization and hypertension or local symptoms consistent with abdominal obstruction. Although most cas- es of ACC are of sporadic origin, they may also occur as part of a congenital or familial disease in which the genetic ab- normalities are well established. ACC can also be discovered incidentally in asymptomatic individuals. In sporadic ACC, some molecular modifications are commonly observed (i.e., overexpression of insulin-like growth factor II or vascular en- dothelial growth factor and somatic mutations of tumor pro- tein 53). When surgical resection of the tumor is impossible or ineffective, chemotherapy with etoposide, doxorubicin and cisplatin plus mitotane or with streptozotocin plus mi- totane is frequently used; however, the overall survival rates are disappointing. Conclusions: Hormonal evaluation is es- sential to diagnose ACC and the prognosis depends on many factors. New treatments, such as insulin-like growth factor I receptor antibodies, tyrosine kinase inhibitors and other antiangiogenic compounds, are now being intensively investigated to identify better therapies for this extremely severe malignant neoplasia. Copyright @ 2009 S. Karger AG, Basel
Introduction
Adrenocortical tumors are relatively frequent clinical entities. They are incidentally discovered on 3 to 4% of abdominal images and in as many as 10% of patients at autopsy. In a series of 380 patients with adrenal inciden- talomas who underwent surgery, the final diagnosis ranged from a harmless adenoma in 52% to potentially lethal cancer or pheochromocytoma in 12 and 11% [1].
Adrenocortical cancer (ACC) is a rare disease with a poor prognosis. Its reported incidence is 1 to 2 cases per million [2]; however, this is probably underestimated. Age distribution shows two peaks, the first occurring in early childhood and the second between age 40 and 50 years. Females are more frequently affected. Sequelae can include Cushing syndrome, virilization and hyperten- sion or local symptoms consistent with abdominal ob- struction. ACC can also be discovered incidentally in asymptomatic individuals.
Molecular Tumorigenesis
Although most cases of ACC are of sporadic origin, they may also occur as part of a congenital or familial disease [3] in which the genetic abnormalities are well established. These include:
· Li-Fraumeni syndrome (p53 at 17p13 locus): character- ized by susceptibility to breast carcinoma, soft tissue sarcoma, brain tumors, osteosarcoma, leukemia and
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ACC. Possible component tumors are melanoma, go- nadal germ cell tumors and carcinoma of the lung, pancreas and prostate.
· Wiedemann-Beckwith syndrome (11p15 locus): over- growth disorder characterized by macrosomia, mac- roglossia, organomegaly and developmental abnor- malities (particularly abdominal wall defects with exomphalos). Patients are at higher risk of developing embryonal tumors such as Wilms tumor, ACC, neu- roblastoma and hepatoblastoma [4].
· Multiple endocrine neoplasia type 1 (11q13 locus): characterized by principal clinical features including tumors of the parathyroid glands, anterior pituitary and endocrine pancreas with thymic carcinoids, thy- roid adenomas and adrenocortical adenomas.
· Carney complex (2p16, 17q22-24): characterized by cardiac and cutaneous myxomas, spotty pigmented le- sions of the skin and endocrine disorders, including primary pigmented nodular adrenocortical hyperpla- sia-producing hypercortisolism, pituitary growth hor- mone adenomas and testicular tumors.
Investigation of the clonal composition of adrenal tu- mors reveals that adrenal carcinomas are monoclonal, whereas adrenal adenomas may be polyclonal in approx- imately 25-40% of cases.
In sporadic ACC, about 85% of cases overexpress in- sulin-like growth factor (IGF)-II. The loss of heterozy- gosity (LOH) of chromosomal locus 11p.15 may lead to an overproduction of IGF-II, which likely has a role in adrenal tumorigenesis.
In sporadic ACC in adults, somatic mutations of tu- mor promoter 53 (TP53) are found in only 25% of cases and are located in four ‘hot spot’ regions within exons 5 and 8 [4]. A more recent study suggests a TP53 mutation rate of 70% in ACC [5]. LOH at 17p13 has been consis- tently demonstrated in ACC [6], where it occurs in 85% of cases and is extremely rare in benign adrenocortical adenomas. The expression of vascular endothelial growth factor is higher in patients with ACC compared with pa- tients with adrenal adenomas [7].
Clinical Features from Diagnosis to Prognosis
Patients with functioning ACC (approximately 60% of cases) often present with signs and symptoms of adrenal steroid hormone excess, although hypersecretion of an- drogens in males or estrogens in females may go unno- ticed. The same holds true for hypersecretion of steroid precursors (17-a-hydroxy-progesterone and deoxycorti-
Table 1. Hormonal work-up for patients with ACC
Low-dose dexamethasone cortisol suppression test, 24-hour urinary free cortisol excretion Baseline serum DHEAS, 17-a-hydroxyprogesterone Baseline serum 17-ß-estradiol (men only) Baseline serum testosterone, androstenedione Serum aldosterone and plasma renin activity 24-hour urinary catecholamines or metanephrines excretion
DHEAS = Dehydroepiandrosterone sulfate.
costerone), which are frequently detected in seemingly nonfunctioning tumors. Cushing syndrome, with or without virilization, is the most frequent presentation in functioning ACC.
Key symptoms of this syndrome are skin atrophy, muscle weakness, hyperglycemia, hypertension and psy- chiatric disturbances. Androgen excess in women leads to hirsutism, male pattern baldness, deepening voice, breast atrophy and menstrual abnormalities. Estrogen excess in men leads to gynecomastia and testicular atro- phy; women may experience breast tenderness and irreg- ular menstrual bleeding.
Aldosterone hypersecretion in ACC is rare and may lead to hypokalemia and hypertension. In children, adre- nal sex steroid excess is common and may lead to viriliza- tion and precocious pseudopuberty.
Patients with nonfunctioning ACC usually present with symptoms related to the local mass effect, i.e., ab- dominal fullness, pain, indigestion, nausea and vomit- ing. Weight loss, low-grade fever and weakness have also been observed in a small number of patients.
Since tumors tend to be large at diagnosis, an abdom- inal mass may be palpable in a significant percentage of patients. The initial manifestation may also be related to metastatic disease (pathologic fracture, bone pain). A substantial and apparently increasing number of patients are diagnosed incidentally during abdominal imaging.
An endocrine evaluation is essential for classification of the tumor as secreting or nonsecreting (table 1). How- ever, it has recently been shown that a specific pattern of hormonal steroid precursors is also present in apparently nonsecreting ACC [8]. The prognosis of ACC is very poor and dependent on many factors (table 2). IGF-II overex- pression and allelic losses at 17p13 have been suggested as useful markers of malignancy [4, 6, 9]. Immunohisto- chemistry of cyclin E or Ki67, which are higher in malig- nant adrenocortical tumors, has also been suggested as potentially useful tools [10, 11].
Table 2. Prognostic factors in ACC
Tumor size Histological parameters (Weiss score) Tumor biology (IGF-II, 17p13 locus, cyclin E, Ki67, etc.) Complete or incomplete resection Age at diagnosis Tumor secreting Number of mitoses in the tumor
| Tumor stagingª | WHO/UICC, 2004 | Proposed by Ens@t, 2008b |
|---|---|---|
| Stage I | T1, N0, M0 | T1, N0, M0 |
| Stage II | T2, N0, M0 | T2, N0, M0 |
| Stage III | T3, N0, M0 or | T3-4, NO, M0 or |
| T1-2, N1, M0 | T1-3, N1, M0 | |
| Stage IV | T4, N0, M0 or | T1-4, N0-1, M1 |
| T 3, N1, M0 or T1-4, N0-1, M1 | (only metastatic disease) | |
a T1 = < 5 cm; T2 = >5 cm; T3 = tumor infiltration locally reaching neighboring organs; T4 = tumor invasion of neighboring organs; N1 = positive lymph nodes; M1 = distant metastasis.
b Ens@t: European Network Study of Adrenal Tumor.
Imaging
In a series of 210 patients with incidental findings of an adrenal mass, a cutoff level of 5 cm yielded a sensitiv- ity for carcinoma of 93% and a specificity of 63% [12]. Four main types of imaging are used to characterize ad- renal tumors:
· Computed tomography (CT): Enhanced CT imaging can reveal a large, low-attenuation suprarenal mass containing areas of high attenuation that are consis- tent with hemorrhage. The lesion appears heteroge- neous and commonly contains central necrosis and calcifications. Hounsfield units (HUs) may help dis- tinguish between benign and malignant tumors; a density >20 HUs suggests a malignant neoplasm [13].
· Magnetic resonance imaging (MRI): With T2-weighted MRI, a malignant lesion usually shows up more in- tensely than the liver. Heterogeneous T1 and T2 sig- nals on MRI are due to the presence of hemorrhage and necrosis within the lesion. In general, metastases and carcinomas contain larger amounts of fluid than adenomas and appear hyperintense on T2-weighted images. Chemical shift imaging is an MRI technique used to detect lipid content in an organ and is the most sensitive method for differentiating adenomas from malignant lesions. In adrenal masses that do not con- tain lipids (metastases or ACC), there is no significant
loss of signal on out-of-phase images; therefore, the signal intensity of the adrenal gland is the same on in- phase and out-of-phase images. There is no loss of sig- nal intensity (i.e., washout) on delayed postcontrast out-of-phase images. ACC can contain areas of intra- cytoplasmic lipid, which results in confined loss of sig- nal intensity on out-of-phase images.
· Scintigraphy with iodocholesterol: In general, there is no uptake by the tumor on scans obtained using this method. However, scintigraphy may be helpful in some situations since adrenocortical adenomas typi- cally give positive scintigraphy results [4].
· Positron emission tomography (PET): Recent studies have shown a consistently high uptake of [18F]fluoro- 2-deoxy-D-glucose (18F-FDG) by malignant adrenal tumors. As a result, 18F-FDG PET scans may play a vi- tal role in distinguishing benign from malignant ad- renal tumors and could positively impact life expec- tancy through early confirmation of metastatic lesions [14]. This simple, nontraumatic imaging procedure should be part of the extensive work-up where avail- able [15].
Histological Parameters
The job of distinguishing malignant tumors from be- nign adrenocortical lesions is not always easy for the pa- thologist [4]. Tumor size and histomorphological features are presently the two main criteria for distinguishing be- tween benign and malignant adrenocortical tumors [16, 17]. There is not a single pathological feature that allows diagnosis of a malignant adrenocortical tumor. A combi- nation of various histological parameters that allow the establishment of a ‘score’ for a given tumor has been de- veloped. The most widely used is the Weiss score, which is made up of nine different parameters (i.e., nuclear grade, mitotic rate, atypical mitosis, character of cyto- plasm, architecture of tumor cells, necrosis, invasion of venous structures, invasion of sinusoid structures and in- vasion of the capsule of the tumor). Each parameter is given a value of one if present and zero if absent. The score is obtained through addition of all the values for each parameter. Following publication of Weiss’s initial paper in 1984, a score of more than three was believed to indicate the presence of a malignant tumor [16]. Over the past two decades, however, it has become clear that the Weiss score has limitations and accurate diagnosis de- pends on the experience of the pathologist. Some patients with a score of three have been diagnosed with benign
tumors and in some rare cases, patients with a Weiss score of two have had malignancies [4, 18]. Because of these limitations, there is a need to develop molecular markers to identify malignancies.
Treatment of ACC
Surgery
For stage 1 to 3 ACC, surgical resection of the adrenal mass is the treatment of choice. Surgery may also be used to treat patients with stage 4 disease. Since long-term re- mission relies on complete tumor removal [4, 19, 20], open adrenalectomy is currently recommended when malignancy is suspected (based on tumor size and imag- ing features). There may be a high risk of peritoneal dis- semination with laparoscopic removal of malignant ad- renocortical tumors [4, 21]. Supplemental glucocorticoid therapy should be started after surgical resection of cor- tisol-secreting tumors to avoid adrenal insufficiency. For stage 4 ACC with distant metastases, tumor debulking can both improve prognosis and reduce steroid excess [4]. Tumor debulking may also help improve the results of other therapies. Surgical removal of limited metastases can also be appropriate. Radiofrequency thermal abla- tion of liver and lung metastasis <4 to 5 cm in maximal diameter can be an alternative to surgical removal [4, 22].
Chemoembolization has also been used to treat liver metastases. Surgical treatment of bony metastases may reduce fracture risk and alleviate neurological symptoms in patients with spinal localization [4].
Radiation Therapy
Radiation therapy is typically ineffective at control- ling tumor growth. However, it has been recently sug- gested that tumor bed radiation therapy may prevent lo- cal recurrence after surgical removal. In patients with bone mestastases, radiotherapy can be used as a palliative treatment to reduce pain and limit the risk of develop- ment of local complications (neurological symptoms, fracture or both) [4].
Medical Therapy
Mitotane in Advanced ACC
When complete tumor removal is not possible or the disease recurs, medical treatment with o,p’DDD (ortho, para’, dichloro-, diphenyl-, dichloroethane, or mitotane) is recommended [4]. Mitotane inhibits cortisol action and steroid synthesis by activating steroidogenic enzymes
(e.g., 11ß-hydroxylase) and inducing cholesterol side chain cleavage. The action of mitotane is specific to the adrenal cortex. Interestingly, mitotane also has a cyto- toxic effect on the adrenocortical cells, which is the ratio- nale for its use in ACC. It effectively controls steroid ex- cess in patients with secreting ACC. Most reports in the literature on the efficacy of mitotane in ACC are retro- spective analyses that give variable results on tumor re- gression. A recent review reports that objective tumor re- gression was evident in 25% of cases [4, 23].
However, the adverse effects of mitotane (mainly di- gestive and neurological) often limit the ability to reach this suggested optimal level [4]. In fact, more than 80% of patients treated with mitotane have reported at least one adverse event: gastrointestinal disturbances (diarrhea, nausea, anorexia); central nervous system complications (lethargy, somnolence, ataxia, dizziness, confusion); hep- atotoxicity; hypercholesterolemia; adrenal insufficiency; gynecomastia and impotence in males; flushing of the skin, decreased platelet aggregation; and leukopenia. Al- though the daily dose required to achieve optimal blood levels varies from patient to patient, there is consensus among treating physicians that the effective dose range for mitotane in the treatment of ACC is between 14 and 20 mg/l [4] . Therefore, close monitoring of blood levels is essential to optimize efficacy and minimize toxicity. Since mitotane treatment can induce adrenal insufficien- cy, supplemental glucocorticoid and mineralocorticoid therapy should be initiated [4]. However, it seems reason- able to propose mitotane as first-line treatment for ad- vanced ACC [24]. In cases of failure or recurrence, sec- ond-line cytotoxic chemotherapy is recommended.
Adjuvant Mitotane Therapy in ACC
Due to the poor prognosis of ACC, adjuvant mitotane treatment after apparently complete tumor removal might be considered for patients with certain prognostic factors (e.g., older age, advanced disease stage or higher Weiss [histologic] score) (table 2). A recent Italian study demonstrated that adjuvant mitotane may prolong recur- rence-free survival [25]. This study included 177 patients with ACC who had undergone radical surgery at 8 centers in Italy and 47 centers in Germany between 1985 and 2005. Adjuvant mitotane therapy was administrated to 47 Italian patients after radical surgery (mitotane group), whereas 55 Italian patients and 75 German patients (con- trol groups 1 and 2, respectively) received no adjuvant treatment after surgery. Recurrence-free survival was significantly prolonged in the mitotane group compared with the control groups. Median recurrence-free surviv-
Randomization
EDP + Mitotane
Streptozotocin + Mitotane
Evaluation every 56 days In case of progressive disease switch the regimen
EDP + Mitotane
Streptozotocin + Mitotane
al was 42 months in the mitotane group versus 10 months in control group 1 and 25 months in control group 2. Hazard ratios for recurrence were 2.91 and 1.97 in control groups 1 and 2, respectively [25]. Despite these positive results, there is still no general consensus on the use of mitotane in this setting [26]. A prospective, multicenter, international trial is planned to determine the role of ad- juvant mitotane in the treatment of patients with certain poor prognostic factors.
Medical Treatment with Cytotoxic Chemotherapy
Several cytotoxic chemotherapy regimens have been used to treat patients with ACC. These regimens are typ- ically reserved for the treatment of patients with tumor progression or intolerability to high-dose mitotane ther- apy. Various drug combinations have been used, but the experience is still limited. According to the Ann Arbor International Consensus Conference on ACC [27], etopo- side, doxorubicin and cisplatin (EDP) in combination with mitotane [28] or streptozotocin plus mitotane [29] are the most widely used treatments. The EDP regimen consists of 4 days of etoposide 300 mg/m2, doxorubicin
40 mg/m2 and cisplatin 80 mg/m2 repeated every 28 days. In a prospective, multicenter, phase II trial conducted in 72 Italian patients with measurable disease not amenable to radical surgery [28], EDP was administered concomi- tantly with mitotane (4 g/day). The overall response rate was 49% (5 patients achieved a complete response and 30 a partial response). Median time to progression in re- sponding patients was 18 months.
The streptozotocin regimen consists of 5 days of strep- tozotocin, 1 g, followed 21 days later by a single dose of 2 g, with mitotane given daily. In one study, 40 patients with ACC (median age 44 years) were treated with oral mitotane (1 to 4 g daily throughout the treatment period) plus intravenous streptozotocin as noted above. This ad- juvant therapy had significant effects on disease-free interval (p = 0.02) and survival (p = 0.01) compared with no therapy after complete resection. Complete or partial response was obtained in 36% (8/22) of patients with measurable disease. Overall 2-year and 5-year survival rates were 70 and 33%, respectively, with the adjuvant treatment. The presence of metastases at diagnosis was identified as a poor prognostic factor (p = 0.02). The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) (fig. 1) is currently under way to compare the results of these two treatments [23]. To date, 190 pa- tients (of a total of 300 planned) have been enrolled.
Conclusions
Unfortunately, for a considerable number of patients, EDP plus mitotane or streptozotocin plus mitotane will be ineffective, and so third-line treatments are desper- ately needed. Trials with IGF-I receptor antibodies, tyro- sine kinase inhibitors and other antiangiogenic com- pounds are being investigated to identify more effective therapeutic options for patients with this extremely se- vere form of malignant neoplasia.
Disclosure Statement
A.P. declares no conflict of interest. V.B. declares no conflict of interest. F.M. declares no conflict of interest.
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