Daniel Kopf · Peter E. Goretzki · Hendrik Lehnert Clinical management of malignant adrenal tumors
Received: 5 May 2000 / Accepted: 28 May 2000
Abstract Malignant primary adrenal tumors are rare forms of cancer with an estimated incidence of two to ten new cases per one million inhabitants per year. The 5-year survival rate for adrenocortical carcinoma is approximately 35%, whereas the 10-year survival rate of malignant pheochromocytoma reaches 40%. Clinical studies support repeated surgery as the mainstay of treatment, either with curative or palliative intention. For adrenocortical carcinoma, adjunctive treatment with oral mitotane leads to well-documented improve- ment of survival. Rare malignant pheochromocytomas with distant metastases are preferably treated by 131I- MIBG. Chemotherapy is reserved for unresectable tumors without sufficient response to mitotane or 131I- MIBG, respectively. Cisplatin and etoposide as single therapy, or in combination with doxorubicine or eto- poside, appear to be effective in adrenocortical carci- noma. Malignant pheochromocytoma may be treated with vincristine, dacarbazine, and cyclophosphamide. Treatment with octreotide is currently being evaluated. Radiotherapy is indicated if unresectable tumor masses cause local symptoms. If symptoms of endocrine activity are not sufficiently controlled by measures aiming at tumor mass reduction, specific inhibitors of hormone synthesis or action are available. Ketoconazole is widely used for adrenocortical carcinoma, and phenoxybenz- amine and metyrosine are available for malignant pheochromocytoma. This review provides guidelines for rational disease management based on still scanty clinical evidence.
D. Kopf . H. Lehnert ☒
Department of Endocrinology and Metabolism, Otto von Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany Tel .: +49-391-6715445; Fax: +49-391-6715448 e-mail: hendrik.lehnert@medizin.uni-magdeburg.de
P. E. Goretzki Department of Surgery, Heinrich Heine University Düsseldorf, Germany
Key words Adrenocortical carcinoma . Malignant pheochromocytoma
Introduction
Adrenal carcinoma and malignant pheochromocytoma are rare tumor entities. Due to the heterogeneous pre- sentation of patients with malignant primary adrenal tumors, randomized controlled studies are scarce and difficult to conduct. Nevertheless, various treatment strategies have been thoroughly evaluated in several studies including considerable numbers of patients. Thus, therapeutic concepts based on solid experimental and clinical evidence are emerging.
Treatment is performed with curative intention in localized tumor stages. In advanced disease, highly individualized treatment goals include surgical mass reduction, control of endocrine activity, and alleviation of symptoms from local tumor growth. The range of therapeutic tools to target specific goals has expanded. Classic pharmacological treatment modalities and antineoplastic chemotherapy have been complemented by more experimental endocrinological and immuno- logical interventions. Radiological strategies include local irradiation and systemic application of specific radioisotope-coupled agents. Surgical techniques have recently been expanded by minimal invasive techniques.
Available studies provide guidelines to orchestrate these tools in an individualized, target-oriented manner. This paper reviews the evidence of established treatment strategies and the potential of existing experimental approaches.
Epidemiology
Since most national cancer registries do not classify malignant adrenal tumors as specific entities, only in- direct estimates of incidence and prevalence are available. Such estimates for adrenal carcinoma and
malignant pheochromocytoma are in the range of three to four new cases per million inhabitants (Mundschenk et al. 1998a). According to older data (Third National Cancer Survey) (National Cancer Institute 1975; Hutter and Kayhoe 1966), the incidence was estimated to be lower with between 0.5 and 2 per million inhabitants. However, increasingly sensitive imaging techniques have led to a more frequent detection of adrenal incidentalomas, and among them some previously unsuspected adrenocortical carcino- mas. In a large series of unselected adrenal tumors, malignant pheochromocytomas were slightly less fre- quent than adrenocortical tumors (Proye et al. 1994; Kolomecki et al. 1999; Kasperlik-Zeluska et al. 1997). Thus, the true incidence of adrenocortical carcinomas can now be estimated to be somewhere between two and ten per million inhabitants. Women are overrep- resented and, while this tumor can occur at any age, they appear to peak around the fifth decade (Wooten and King 1993). In malignant pheochromocytoma, the sex ratio is more balanced and age distribution equals that of adrenocortical carcinomas (Averbuch et al. 1988; Krempf et al. 1991; Mornex et al. 1992; Kopf et al. 1997; Plouin et al. 1997).
For both diseases, distinctive childhood tumor types exist. Adrenomedullary malignant tumors in childhood are classified as neuroblastoma. In parallel, childhood adrenocortical cancer seems to have a distinct biology and is believed to be of embryonic origin (James et al. 1999).
Other rare malignant tumor types with primary location in the adrenal region include lymphoma, his- tiocyto-sarcoma, leiomyosarcoma, germinal tumors, and schwannomas (Proye et al. 1998; Wu et al. 1999; Pit- tasch et al. 2000). Differential diagnoses of malignant lesions in the adrenal glands must consider metastases of other tumors, particularly malignant melanomas, renal, breast, and bronchial carcinomas.
Based on autopsy and imaging studies, an estimated 1-3% of persons older than 50 years show adrenal nodules. Even in a series of 469 adrenal masses treated by surgery only one-fourth (106) were malignant: 17 metastases and 89 primary adrenal tumors (Proye et al. 1998). Among these, 37 were malignant pheochromo- cytomas and 45 were adrenocortical tumors. The remaining were non-adrenal tissue malignant lesions, which developed in the adrenal fossa.
The majority of pheochromocytomas are benign. More recent studies report malignancy rates among pheochromocytoma of between 17 and 26% (Mornex et al. 1992; Proye et al. 1992). A synopsis of three large series of pheochromocytoma found malignant behavior in 15.5% (Proye et al. 1994).
Prognosis in malignant adrenal tumors is poor. In a series of adrenal carcinomas from the Memorial Sloan- Kettering Cancer Center, overall survival rate was 36% at 5 years and median survival was 28 months (Harrison et al. 1999). For pheochromocytoma, our own experi- ence shows a somewhat better prognosis with 40%
survival after 10 years (Lehnert 1995). However, there is a wide range of clinical presentation, with patients in whom the disease leads to rapid deterioration and death within less than 2 years, and other patients with a more benign course (Averbuch et al. 1988).
Adrenocortical carcinoma
Pathogenesis
Adrenal carcinomas are monoclonal lesions. Various somatic mutations have been found, which may con- tribute to the malignant phenotype. Overexpression of growth factors and loss of tumor suppressor genes play an important role in pathogenesis. Elevated expression of insulin-like growth factor II (IGF II) (Ilvesmaki et al. 1993; Logie et al. 1999), transforming growth factor «, and epidermal growth factor (Sasano et al. 1994) has been demonstrated and is believed to contribute to malignant growth.
Since the IGF II gene shares its chromosomal locus (11p15) with two additional candidate genes, the tumor suppressor genes p57(kip2) and H19 (Gicquel et al. 1997; Voutilainen et al. 1998), loss of heterozygosity or pathological imprinting has been demonstrated for this region in a high proportion of adrenocortical carcino- ma and may be useful in differentiating between benign and malignant lesions. The increased expression of IGF II and simultaneous loss of the p57(kip2) tumor sup- pressor gene which encodes for a cyclin-dependent kinase may disturb regulation of G1/S phase (Gicquel et al. 1997). Loss of this gene leads to enhanced activity of G1 cyclin/cyclin-dependent kinase complexes, which in turn promotes cell proliferation (Bourcigaux et al. 2000).
Loss of heterozygosity has also been demonstrated for chromosome 17p13. In contrast to the changes in IGF II expression, genomic aberrations with a gain of chromosome 17 can be found in benign hyperplastic lesions (Zhao et al. 1999), pointing to an early role in tumorigenesis. Among other genes, this region contains the tumor suppression gene p53. In an immunohisto- chemical study, expression of p53 was higher in adrenocortical carcinoma than in adenoma (McNicol et al. 1997) and mutations in the p53 gene were found more frequently in malignant tumors (Reincke et al. 1994). Additionally, germ line mutations of p53 predis- pose to childhood adrenocortical cancer (Sameshima et al. 1992; Wagner et al. 1994).
Mutations of the ret proto-oncogene, which is responsible for multiple endocrine neoplasia type 2, have been demonstrated in a minority of adrenocortical tumors. The functional significance of these findings remains to be clarified (Lin et al. 1998). Conversely, mutations of the MEN 1 gene have not been detected in sporadic adrenal neoplasias (Gortz et al. 1999).
Overall, genetic tools may become helpful instru- ments in diagnosis, particularly for differentiating
benign from malignant lesions in biopsy specimen (Gicquel et al. 1997), but at present they are still of mainly scientific interest.
Clinical presentation
Most patients with malignant adrenocortical tumors are symptomatic at the time of diagnosis, either because of endocrine disturbances or local problems due to large, endocrine-inactive tumors. A growing number of asymptomatic patients are identified during evaluation of adrenal incidentalomas, e.g., by ultrasound. Approximately two-thirds of patients exhibit clinical signs of endocrine disturbances at presentation, with Cushing’s syndrome accounting for more than half of endocrine symptoms. Furthermore, virilizing or femi- nizing symptoms are encountered in a substantial pro- portion of patients, whereas signs of mineralocorticoid excess are less frequent (Vassilopoulou-Sellin et al. 1993; Haak 1994; Bellantone 1997; Luton 1990; Proye 1998; Kasperlik-Zaluska 1995).
Subtle endocrine disturbances which do not lead to striking clinical symptoms, can be detected in a thor- ough laboratory work-up in most patients. In rare cases, paraneoplastic secretion of hormones which are not typical for the adrenal gland is encountered. Among others, acromegaly or inappropriately high ACTH secretion in the presence of Cushing’s syndrome have been described (Law et al. 1988; Kasperlik-Zaluska et al. 1995). It is also important to note that endocrine activity varies in the course of the disease: primarily, endocrine-inactive tumors may change into active tumors and vice versa, the pattern of hormone secretion may vary, and combinations of various hormones are encountered.
Other non-hormone-induced symptoms include abdominal pain, lumbar pain, weight loss, weakness, fever, or palpable abdominal masses (Kasperlik-Za- huska et al. 1995) or symptomatic hypoglycemia (Luton et al. 1990). Metastases were present at the time of diagnosis in 30-40% of cases (Luton et al. 1990; Haak et al. 1993).
The description for the extent of the disease follows the TNM classification, which is also the basis for a clinical tumor staging (MacFarlane 1958; Sullivan 1978) (Table 1).
In a study of patients in the Italian Registry for Adrenal Cortical Carcinoma, 92 (48.9%) out of 188 patients were in stages I and II, i.e., disease was limited to the adrenal gland, 65 (34.6%) patients were in stage III (disease confined to the region), and 30 (16.0%) patients had distant metastases (Bellantone et al. 1997). Considering the mostly large tumors (mean tumor weight was 532 g in the study of Luton et al. 1990), it is surprising that adrenocortical carcinoma mainly pre- sents as a regional problem with only few cases of synchronous distant metastases to liver, lung, and bones.
Diagnosis
Preoperative diagnostic procedures include imaging techniques and evaluation of endocrine disorders. In estimating the probability of benign or malignant le- sions size is an important criterion, which may be measured by ultrasonography. In a series of 210 patients with incidental findings of an adrenal mass, a cut-off level of 5 cm yielded a sensitivity for carcinoma of 93% with a specificity of 63% (Terzolo et al. 1997). Similar data have been reported with a cut-off size of 6 cm (McLeod et al. 1993). Computed tomography and MRI may be of additional help in small tumors and in tumors with questionable malignancy. With both techniques the diagnosis of myelolipoma, cysts, and hemorrhages into the adrenal gland can undoubtedly be established. Ad- renal adenomas typically show a low radiological den- sity with regular appearance and clear margins, while carcinomas are mostly large tumors with irregular margins or infiltration into other organs. Carcinomas may additionally demonstrate central necrosis, internal hemorrhage, and peripherally enhanced nodules in MRI (Schlund et al. 1995; Angeli et al. 1997; Szolar et al. 1999). One must keep in mind, however, that some
| T | N | M | |||
|---|---|---|---|---|---|
| NO | No lymph nodes involved | M0 | No distant metastases | ||
| T1 | Tumor < 5 cm, no invasion of surrounding tissue | N1 | Regional lymph nodes involved | M1 | Distant metastases present |
| T2 | Tumor > 5 cm, no invasion | ||||
| T3 | Local tumor growth without infiltration of adjacent organs | ||||
| T4 | Infiltration of surrounding organs | ||||
| Stages | |||||
| I | T1 N0 M0 | ||||
| II | T2 NO MO | ||||
| III | Every T with regional extension and/or N1 | ||||
| IV | Distant metastases |
larger adenomas may be misinterpreted as carcinoma preoperatively (Newhouse et al. 1999).
Since adrenocortical carcinomas primarily metasta- size into regional lymphatic tissue the assessment of paraaortal lymph nodes is important. As tumors then metastasize predominantly into lung and liver, ini- tial staging of adrenocortical carcinomas includes conventional chest X-ray or CT of the thorax and an ultrasonography or CT of the liver. The use of 131I- methylnorcholesterol, which visualizes adrenocortical tumors with normal or increased endocrine function, is of little help, however, in differentiating between benign and malignant lesions (Pasieka et al. 1992).
Even though histological evaluation of resected tumors can leave some uncertainty in the differentiation between malignant and benign lesions, some histological findings have prognostic significance: tumor size, hem- orrhage, and mitotic count are prognostically unfavor- able features (Harrison et al. 1999). Cytogenetic studies may aid in differentiating carcinoma from adenoma (Lu et al. 1996).
During endocrine work-up, increased plasma cortisol, testosterone, aldosterone, estrone, estradiol, androstendione and androstendiol, urinary 17-OH-cor- ticosteroids, and 17-ketogenic steroids have been reported. As the endocrine profiles of tumors change in the course of the disease, clinical relevance of exact identification of involved steroids remains unclear. A minimal endocrine evaluation should be performed in all patients. In our opinion, this should include basal cortisol, cortisol after dexamethasone, testosterone, and DHEAS. Additional tests should be chosen according to individual symptoms.
Treatment strategy and surgery
A general outline of therapeutic strategies is given in Fig. 1. Only complete resection (Ro resection) of tumor and surrounding lymphatic tissue promises potential cure (Lee et al. 1995). Although tumor relapse occurs in up to 37% of all Ro-resected patients (Bellantone et al. 1999) complete resection is still the best individual factor for a good prognosis and prolonged survival (Pommier et al. 1992; Schulick et al. 1999). In the hands of expe- rienced surgeons morbidity and mortality of such surgery is low (Favia et al. 1995). If Ro resection is not possible, surgical debulking can be intended to increase the efficacy of subsequent adjuvant therapies (Bukowski et al. 1993). This is even indicated in patients with advanced tumor stage, with local invasion or remote metastases (Stages III or IV).
Ro resection as well as incomplete resection is followed by adjuvant mitotane treatment. Mitotane treatment should also be tried in those few patients who are primarily inoperable.
While minimally invasive techniques are available for adrenalectomy in benign disease, this does not appear to be the appropriate technique in malignant adrenal
Stage I
Stage II
Stage III
Stage IV
Attempt Ro resection
Surgical debulking whenever possible
Mitotane
Progressive / recurrent disease
Reoperation whenever possible
Ro resection
Residual tumor or metastases
Mitotane + chemotherapy (+ endocrine control + radiotherapy of metastases as needed)
Mitotane
tumors (Mancini et al. 1999). Malignant disease requires thorough exploration of the entire region.
In all situations, attempts to reduce tumor load must be escorted by distinct strategies to control endocrine activity, according to the extent of endocrine hyper- function.
It is of critical importance to reconsider surgical intervention and reoperation at any point in the course of disease, since debulking increases the efficacy of all adjuvant measures and improves prognosis (Pommier et al. 1992; Crucitti et al. 1996), allowing improvement of symptoms and survival up to 5 years after recurrence (Jensen et al. 1991).
Radiotherapy
For radiotherapy, only anecdotal data or very small patient series with different tumor stages are available (Magee et al. 1987; Markoe et al. 1991; de Castro et al. 1993). Lack of control patients limits interpretation of these data. They do not support a general recommen- dation of adjuvant radiotherapy after complete resec- tion. Radiation may improve local control in stages III or IV, where Ro resection is difficult to perform. In the retrospective study of Markoe and co-workers, patients
in stage III received 50-60 Gy in daily fractions of 1.5- 1.8 Gy over 5-7 weeks. Survival ranged from 34 months to 7 years, suggesting moderate improvement compared to historic controls.
There is consensus about radiation therapy of bone metastases indicated in cases of impending instability, fractures or pain. However, skeletal metastases are present in only about 10% of adrenal carcinoma.
Mitotane
Even though no prospective studies are available, a growing body of evidence supports the use of mitotane as adjunctive treatment in various settings. Mitotane (chemical name: 1,1 dichloro-2-(o-chlorophenyl)-2-(p- chlorophenyl)ethane, o,p’-DDD) has effects on normal and on tumor tissue- producing steroids. This com- pound inhibits cholesterol side chain cleavage (P450scc) and 11-ß hydroxylation (P450c11), the latter leading to accumulation of 11-deoxycortisol. Measurable free uri- nary cortisol is reduced. Mitotane also modifies hepatic metabolism of corticosteroids. More importantly, mitotane causes structural damage to mitochondria in the zona reticularis and zona fasciculata. These cyto- toxic effects on steroid-producing tissue lead to necrosis of vulnerable normal and tumor tissue (Luton et al. 1979; James and Few 1985; Miller and Crapo 1993).
The clinical efficacy of mitotane treatment and out- come are heterogeneous. In the classic large study of Luton and co-workers, hormone secretion was effec- tively controlled in 75% of patients. In this study, treatment did not have an effect on survival, as was the case in another study including 19 patients (Vassilop- oulou-Sellin 1993). In contrast, other studies found improved survival (Haak et al. 1994; Kasperlik-Za- huska1995), including cases with complete remission documented up to 4 years in a patient with local lymph node involvement (Boven 1984; Decker et al. 1991).
The key to these discrepancies may lie in the time course of treatment and in dosage. In a larger study with a follow-up of more than 20 years, immediate adjunctive treatment with mitotane after surgery was effective in terms of survival. Of 26 patients treated immediately with mitotane regardless of tumor stage, 12 survived in the long term, while out of seven patients treated by surgery only, two survived (Kasperlik-Zahuska et al. 1995). Dose reduction or interruption of treatment resulted in prompt recurrence of disease.
Indeed, there is a dose-response relationship between mitotane serum levels and survival. Primary tumor as well as recurrent tumor responded well to serum levels of more than 15 mg/l, while no response was seen in pa- tients with lower serum levels (Haak et al. 1994).
Treatment is started with a daily dose of 1.5-2.0 g, divided into three or four single doses. Subsequently, dosage is increased to reach a daily amount of 8-12 g. Therapeutic drug monitoring may be helpful to target serum levels above 14 mg/l, or even better above 20 mg/l.
| Gastrointestinal | Approx. 85% |
|---|---|
| Vomiting | 35% |
| Nausea | 20% |
| Diarrhea | 20% |
| Anorexia | 15% |
| Central nervous system | 40% |
| Somnolence, lethargy, ataxia, dysarthria | 25% |
| Vertigo | 15% |
| Skin | 15% |
With these doses, side effects of mitotane are com- mon (see Table 2) and dose-dependent. Most of the side effects are reversible after discontinuation of treatment. More frequent side effects include gastrointestinal symptoms such as anorexia, nausea, and vomiting, and neurological problems such as ataxia, speech difficulty, somnolence, confusion, and lethargy (Boven et al. 1984; Luton et al. 1990; Bornstein et al. 1999). Biochemical side effects such as elevation of transaminases and cho- lesterol occur.
Since mitotane suppresses cortisol production in healthy adrenal tissue, glucocorticoid substitution is necessary. In cases without hormonal activity, substitu- tion has to be initiated at the same time as mitotane. A dose of 20-40 mg of hydrocortisone is recommended, two-thirds of which should be given in the morning, the remaining third in the afternoon. Of course, the substi- tution dose must be increased in special situations such as in the perioperative phase and in intercurrent infec- tions. Most authors also recommend substitution of mineralocorticoids by fludrocortisone, e.g., 0.05 mg in the morning.
Taken together, mitotane treatment is efficacious in terms of endocrine control and survival in a high pro- portion of patients. In order to achieve optimal effects, adjuvant treatment should be initiated in all patients after surgery, while high serum levels should be aimed for.
Cytotoxic chemotherapy
Cytotoxic chemotherapy is used in recurrent or pro- gressive disease despite a treatment with mitotane and in patients with primarily unresectable lesions or recurrent tumors after initially radical surgery. A large number of treatment protocols have been used with 5-fluorouracil, vincristin, doxorubicin, BCNU, and methotrexate, but only in small patient series.
Cisplatin is the most widely used agent. A response rate of 33% (three complete and three partial responses in 18 patients) has been reported for the combination of cispl- atin with etoposide (VP 16) (Bonacci et al. 1998). The protocol used cisplatin in a dose of 100 mg/m2 on day 1 and VP 16 in a daily dose of 100 mg/m2 on days 1-3. Almost similar response rates were reported for a com- bination of 5-fluorouracil, doxorubicin, and cisplatin when combined with mitotane (Schlumberger et al. 1991).
The combination of mitotane with classic cytotoxic chemotherapy has been suggested, based on the finding that mitotane reverses multidrug resistance mediated by MDR-1/P-glycoprotein (Dogliotti et al. 1995) and enhances the effects of anthracyclins (Villa et al. 1999). This approach of combining mitotane with classic cyto- toxic agents has been evaluated in an Italian phase-II trial using etoposide, doxorubicin, and cisplatin in 28 patients with advanced, inoperable disease (Berutti et al. 1998). Doses administered were 40 mg/m2 for cisplatin on days 1 and 9, 20 mg/m2 doxorubicin on days 1 and 8, 100 mg/m2 etoposide on days 5-7, and mitotane 4 g/day. Due to the side effects of this combination, the mitotane dose was, however, less than 4 g per day in most patients. The results in these 28 patients with an advanced inop- erable disease are encouraging and support the concept of a combination of classical cytotoxic agents with mitotane (Bukowski et al. 1993), since the combination may be more effective than was expected from earlier trials (response rate only 30%). Further substances that have been used are suramin, octreotide, and paclitaxel. Suramin was abandoned because of toxic side effects (Arlt et al. 1994). Octreotide lacked any effect in a first trial (Chan et al. 1999), and paclitaxel has as yet only proven effective in in vitro studies (Fallo et al. 1996).
Endocrine control
For patients whose endocrine activity is not adequately suppressed by surgical resection and mitotane, addi- tional inhibitors of steroid production are available.
Ketoconazole
Ketoconazole, an imidazole antifungal agent, inhibits 17,20 desmolase activity of P450c17 and, less effectively, its hydroxylase activity and P450c11ß in vitro (Feldman 1986). Therefore, it is also effective in suppressing androgens in virilizing tumors. According to clinical long-term studies, this agent is effective in suppression of endocrine activity in the long-term and preoperative treatment of Cushing’s disease and adrenocortical car- cinoma (Engelhardt et al. 1994). It does not influence tumor growth and is not effective in controlling endo- crine activity in carcinoma as monotherapy. The maxi- mum daily dose is 200 mg four times daily. Liver toxicity warrants routine control of transaminases and, if nec- essary, an interruption of treatment.
Metyrapone
If the combination of mitotane and ketoconazole fails, metyrapone is a therapeutic option. Metyrapone selec- tively inhibits P450c11 in all zones of the adrenal cortex, thus targeting cortisol production. For treatment of Cushing’s syndrome, it was effective regardless of the etiology of the disease (Thoren et al. 1985). Typically, a
daily dose of 1500 mg (range 750-5000) is required. The most important side effect is suppression of normal ad- renal tissue, necessitating substitution of hydrocortisone.
Other agents
Aminogluthetimide is an inhibitor of P450scc, which has occasionally been used in Cushing’s syndrome (Thoren et al. 1985). Etomidate, an imidazole anesthetic agent, inhibits P450c11 and P450scc. Since it is only available as an intravenous drug, its application in chronic ther- apy is limited.
Malignant pheochromocytoma
Pathogenesis
Very little is known about the pathogenesis of malignant pheochromocytoma, whereas genetic information is available about the development of pheochromocyto- mas in familial syndromes.
Mutations of the ret proto-oncogene encoding a tyrosine kinase-type receptor utilizing glial cell-derived neurotropic factor as its ligand, are known to be responsible for benign pheochromocytoma in the syn- drome of multiple endocrine neoplasia (MEN) type 2 (Mulligan et al. 1998). Another syndrome with familial pheochromocytoma, von Hippel-Lindau (VHL) dis- ease, is caused by a mutation of the VHL-gene on chromosome 3p25 (Latif et al. 1993). However, somatic mutations of the ret proto-oncogene or rearrangement have been found in a minority of sporadic pheochro- mocytomas only. Somatic mutations of the VHL-gene or of the cul2-gene, which interacts with the VHL-gene, are present in few sporadic pheochromocytoma (Var- gas et al. 1997; Duerr et al. 1999; Woodward et al. 1997). The cell cycle regulating gene p53 exhibits frequent mutations or intronic sequence alterations in malignant, but not in benign, pheocromocytoma (Yoshimoto et al. 1998). Loss of heterozygosity has been demonstrated in various regions (1p, 3p, 17p, 22q), which may influence tumor suppressor genes (Lehnert et al. 1998).
Pheochromocytomas frequently secrete additional peptides. While some of them - for example, chro- mogranin A - do not affect clinical presentation, pro- duction of other peptides may mimic different endocrine diseases. Among others, ACTH, parathormone-related peptide, neuron-specific enolase, Interleukin 6, and VIP have been described, sometimes leading to specific clin- ical syndromes (Oisho and Sato 1988; Finkenstedt et al. 1999; Quarles Van Ufford-Mannesse 1999).
Clinical presentation
Clinical presentation does not differ markedly between malignant and benign pheochromocytoma and is mainly
a consequence of markedly elevated hormone synthesis (Lehnert et al. 1997). Patients with malignant disease tend to have larger tumors (90.9 vs 55.7 mm diameter) and higher urinary metanephrines (Plouin et al. 1997), but there is more overlap in size than in adrenocortical carcinoma.
In addition, according to localization of metastases, compression or pain from skeletal metastases may be present. The by far most frequent site of metastases is the skeleton; additional sites are liver, retroperitoneum with lymph nodes, CNS, pleura, and kidney (Lehnert et al. 1997). Malignant pheochromocytoma or para- ganglioma are primarily located outside the adrenal gland in up to 50% (Averbuch et al. 1988).
Diagnosis
Similar to adrenocortical carcinoma, the diagnostic strategies for malignant pheochromocytomas have to consider endocrine activity and tumor localization as well as tumor growth.
Endocrine diagnostic procedures have been evaluated for pheochromocytoma in general, therefore, it is diffi- cult to provide sensitivity and specificity data of malig- nant pheochromocytoma. Diagnostic accuracy is lower for malignant tumors, because some of them may not produce excess catecholamines.
A valuable screening test is a 24-h urinary or over-night excretion of adrenaline and noradrenaline with sensitivity and specificity rates between 80 and 100% (Duncan et al. 1988; Ross et al. 1993). Recently, for the easier over-night collection, a sensitivity of 100% and a specificity of 98% has been reported (Peaston 1996). These data in a small series need further confirmation. In sporadic and heredi- tary pheochromocytoma, plasma metanephrine and nor- metanephrine have been found to be comparable in diagnostic accuracy (Lenders et al. 1995; Eisenhofer 1999). In view of those superior results, measurement of vanillylmandelic acid is obsolete (Graham et al. 1993). For confirmation, particularly in patients with moderate ele- vations of baseline plasma catecholamines, the clonidine suppression test (cut-off 500 ng/1 3 h after oral clonidine 0.3 mg) is a valuable tool with a diagnostic accuracy of 92% in borderline patients (Sjoberg 1992). Therefore, the use of the glucagon test is rarely indicated.
Chromogranin A shows a good correlation with tumor mass and is particularly helpful not only in diagnosis, but also as a tumor marker for detection of recurrence (Stridsberg et al. 1997).
Ultrasound can fairly reliably detect larger tumors and is a good screening technique as an adjunct to the endocrine work-up. However, since small tumors may escape the diagnosis, computed tomography or MRI is warranted in all patients with pathological catecholam- ines with a positive predictive value of 95% for tumor localization (Orchard et al. 1993). MRI appears to be superior in overall sensitivity to computed tomography (98 vs 89%) (Jalil et al. 1998).
Scintigraphy with MIBG (meta-jodo benzyl guani- dine) has almost 100% specificity and a very good sensitivity even in malignant pheochromocytoma. Only one case of a false-positive result has been reported (Letizia 1998). This technique is superior to all other techniques in localizing unknown metastases, if biochemical follow-up suggests recurrent disease or metastases and is thus part of the routine work-up of pheochromocytoma (Sisson et al. 1999b).
Somatostatin receptor scintigraphy (11In-octreotide scintigraphy) is a very valuable adjunct to diagnostic work-up. Its overall sensitivity and specificity is lower than MIBG scintigraphy, but it may detect some MIBG negative tumors or metastases (Tenenbaum et al. 1995; Kopf et al. 1997; Cottin et al. 1999). We recommend including this technique in routine staging of malignant pheochromocytoma. Another imaging technique has just recently been introduced and is promising for detection of MIBG negative lesions: PET with 2-(fluo- rine-18)fluoro-2-deoxy-D-glucose (Shulkin et al. 1999).
Malignancy should be suspected in large, sporadic tu- mors (arbitrary cut-off 5 cm), clinical signs of metastases, or in MIBG positive lesions outside the primary tumor.
Distinguishing between malignant and benign disease may be difficult on the basis of histology alone (Sch- lumberger et al. 1992), and sometimes metastases are detected many years after resection of the primary tumor (Tanaka et al. 1993; Goldstein et al. 1999). Criteria of malignant disease are metastases in non-chromaffin tis- sue, or local tumor invasion (Mundschenk et al. 1998b). Cytogenetic analysis is of little help, since diploid DNA pattern does not necessarily predict benign behavior of the tumor. Telomerase, a nuclear enzyme regulating the number of replications in each cell is overexpressed in many malignant tissues, but does not reliably differen- tiate between benign and malignant adrenal tumors (Bamberger et al. 1999). MIB1, a nuclear proliferation marker may have some predictive value in the diagnosis of malignant disease as well (Brown et al. 1999).
Treatment strategy and surgery
Primary surgical resection is the treatment of choice whenever possible. If disease is limited at time of diag- nosis, then surgical treatment of pheochromocytoma is performed with curative intention. In extended disease, surgery has still to be considered in the first place for debulking and as palliative treatment (Mundschenk et al. 1998a).
As in adrenocortical tumors, minimally invasive techniques have been developed and may be an option for some patients with benign pheochromocytoma (Fig. 2). While bilateral pheochromocytomas are safely operated endoscopically, the need for thorough explo- ration of surrounding tissue and for histological exam- ination of an unfragmented specimen limits the use of this technique if malignancy is suspected (Goretzki et al. 1997; Manger et al. 1997).
Malignant pheochromocytoma with metastases
Surgical debulking whenever possible
MIBG-Scintigraphy
MIBG-positive
MIBG-negative
131I-MIBG therapy
Chemotherapy (Averbuch-Protocol), or Octreotide
Response
No response
Response
No response
Continue in increased intervals (12-18 Mo.)
Continue as in MIBG-negative cases. Reevaluate surgical options
Continue to maximum dose. Reevaluate surgical options
Intensify symptomatic treatment. Reevaluate surgical options
Adrenal-sparing resection is an option mainly for bilateral pheochromocytoma, as it occurs in a number of inherited disorders, namely multiple endocrine neoplasia type 2 and phakomatoses as von Hippel-Lindau disease and von Recklinghausen’s disease (Neumann et al. 1999). In these disorders, adrenal disease virtually always presents as bilateral pheochromocytoma, while malignant pheochromocytoma is extremely rare. Therefore, conventional surgery inevitably leads to hypocortisolism. Patients will need lifelong substitution of hydrocortisone and fludrocortisone. Bilateral adre- nal-sparing tumor enucleation avoids hypocortisolism in almost all cases. Therefore, in the hands of an experi- enced surgeon, this minimally invasive approach cer- tainly poses an intriguing alternative to adrenalectomy in patients with these hereditary syndromes.
On the other hand, sporadic pheochromocytoma is malignant in 17 and 26%, but the primary tumor is almost always confined to one side (Mornex et al. 1992; Proye et al. 1992). As mitotic activity is not a reliable parameter of malignancy in pheochromocytoma, the intact capsule and tumor-free regional lymph nodes are the main factors for benign disease. To definitely preserve the tumor capsule and perform total lympha- decectomy the transabdominal approach is necessary and minimally invasive procedures as well as retro- peritoneal approaches should be abandoned (Orchard et al. 1993).
In the case of malignant pheochromocytoma radical surgery is intended, but to some degree the tumor may persist (Plouin et al. 1997). This will lead to local recurrent tumors, which are treated surgically again for as long as possible. Dependent on tumor localization in paraaortal lymph nodes, the mediastinum or the genito- urinary tract (organ of Zuckerkandl) individual surgical strategies are required.
Although most secondary tumors are local recurrenc- es, no experience with adjuvant pre- and postoperative radiation exists. Extraperitoneal metastases may arise as single lesions that can be excised surgically, but generally they are multiple. Radical surgical resection is often impossible for these, and other treatment modalities such as 131I-MIBG therapy have to be considered.
Pretreatment
Medical pretreatment with phenoxybenzamine is rec- ommended by most authors (Walther et al. 1999). As late as in the 1950s, mortality of surgical resection of pheochromocytoma amounted to 50%. Intraoperative hypertensive crises, postoperative vasodilation and hypovolemic shock, and coronary spasms have compli- cated the perioperative course. Preoperative irreversible a-blockade using phenoxybenzamine has therefore become routine and has been found to improve the peri-
operative course and reduce arrhythmias (Dabrowska et al. 1995; Russell et al. 1998). Alternative regimens include combinations of prazosin, «-methyl-para-tyro- sine (metyrosine) with or without phenoxybenzamine (Steinsapir et al. 1997).
Current guidelines recommend dosages of phenoxy- benzamine up to 160 mg per day, divided into four equal doses every 6 h. These doses are only tolerated if treat- ment is instituted gradually over a 10- to 14-day period. Orthostatic hypotension and nasal congestion are very frequent but tolerable side effects, which should not lead to withdrawal of therapy.
Immediate preoperative and intraoperative volume expansion, usually using isotonic crystalline solutions, are a mainstay of perioperative management.
Owing to improved localization, preoperative medi- cal treatment, and surgical and anesthetic techniques, surgical results have greatly improved and mortality has declined to less than one per cent in experienced hands (Ulchaker et al. 1999).
In a recent report, the value of routine preoperative treatment with phenoxybenzamine has been questioned. This series did not find a difference in outcome or peri- operative course between patients with or without such pretreatment. However, this was not a randomized study and criteria for allocation to pretreatment with phen- oxybenzamine or without this drug were not specified. In addition, this study was an analysis of 113 patients treated in a single highly specialized center over a period of 18 years. It is quite conceivable that in a highly experienced center with a more differentiated patient management, less strict patient management is safe (Ulchaker et al. 1999). The authors of this review feel that in most institutions it is still mandatory to perform routine high-dose pretreatment with phenoxybenzamine until a set of patients who do not benefit from this regimen is clearly identified.
MIBG treatment
131I-MIBG treatment is a well-documented therapeutic option and is the treatment of choice for all unresec- table, MIBG positive tumors (Sisson et al. 1984; Krempf et al. 1991). Five cases with complete remissions up to 58 months have been reported in some cases with this strategy. Hormonal response rates are seen in 45% of patients, tumor responses in 30% (Loh et al. 1997). Soft tissue metastases appear to respond better than bone metastases. Applied single doses range from 3.7 to 9.8 GBq given intravenously over 2-3 h, while cumula- tive doses range from 3.8 to 85.9 GBq. Treatment intervals are 3-6 months with re-evaluation before each additional treatment course. MIBG treatment prolongs survival and is effective in palliative treatment (Tron- cone and Rufini 1997).
One of the advantages of MIBG treatment is that it is well tolerated with minimal toxicity. Multiple treatment courses are possible.
Not all patients with multiple metastases of malignant pheochromocytomas have sufficient uptake of MIBG to allow MIBG therapy. In many patients, MIBG negative lesions coexist with MIBG positive lesions, thus requir- ing combined treatment strategies (Kopf et al. 1997). Rates of eligible patients vary according to the uptake threshold required. In our own experience, it is worth- while re-evaluating previously negative patients from time to time, since there is a slight chance of conversion of MIBG negative to MIBG positive lesions.
Cytotoxic chemotherapy
Unfortunately, only sparse data on chemotherapeutic regimens are available, most of them in reports of few cases. The most well-established regimen is the one proposed by Averbuch and co-workers (Averbuch et al. 1988). They used cyclophophamide 750 mg/m2 body surface area on day 1, vincristine 1.4 mg/m2 on day 1, and dacarbazine 600 mg/m2 on days one and two every 21 days in 14 patients. Complete tumor response was achieved in two patients, partial response in six patients. In only one patient progression was noted. Biochemical response was very similar.
Since the publication of these rather encouraging results, a number of case reports have been published using the same regimen.
There are no clinical data available for different an- tineoplastic agents except for case reports. In one case report of a cardiac malignant pheochromocytoma with lymph node metastases, adjuvant chemotherapy with substances commonly used for neuroblastoma was per- formed (vepeside, carboplatyl, vincristine, and adria- mycin) (Jirari et al. 1999). After 5 years, the patient is reported to be still free of disease. Although a single case report in a patient with limited disease has to be inter- preted very cautiously, the use of neuroblastoma regi- mens in pheochromocytoma may be a promising alternative.
Data from in vitro experiments suggest that cisplatin and doxorubicin increase uptake of MIBG in neu- roendocrine tumor cells (Meco 1999), thus advocating combination of MIBG and chemotherapy. In a recent series of six patients, MIBG treatment was combined with the chemotherapy regimen suggested by Averbuch (Sisson et al. 1999a). Even though partial response was seen in only two patients, the authors interpreted their results as evidence for additive effects of MIBG and chemotherapy.
New treatment options
Treatment with octreotide is currently evaluated in a multi-center study (Mundschenk et al. 1998). This trial is based on the rationale that this combination has an effect on neuroendocrine tumors of the gastrointestinal tract. Somatostatin receptors are present on pheo-
chromocytoma tissue, even though more recent data suggest that SST3 receptors are more abundant than SST2 and SST4, which are responsive to octreotide (Reubi et al. 1992; Mundschenk et al. 2000).
Endocrine control
For blood pressure and symptomatic endocrine control, the covalent «-blocker phenoxybenzamine is the treat- ment of choice. Long-term dosage is 30-50 mg per day, divided into 4-5 doses. It is markedly lower than the doses required for preoperative treatment. Alternatively, other a-blocking agents may be used. Relevant side effects are orthostatic hypotension, reflex tachycardia, miosis, and nasal congestion.
After initiation of x-blockade, a ß-blocker can be given as needed.
In cases with uncontrolled catecholamine excess, alpha-methyl-paratyrosine is used in doses up to 4 g daily. This drug inhibits tyrosine hydroxylase, thus blocking catecholamine biosynthesis. The main prob- lems with this drug are central nervous side effects, owing to competition of this drug for the transport system of long chain amino acids across the blood-brain barrier. Symptoms are sedation, parkinsonism, and nightmares, which occur regularly above a dose of 5 g daily.
Calcium channel blockers reduce catecholamine synthesis and may prevent coronary spasms. They have also been used successfully for intraoperative control of blood pressure (Proye et al. 1989). These and other antihypertensive drugs may be given as needed for control of symptoms from catecholamine excess.
Conclusions
Although adrenocortical carcinomas and malignant pheochromocytomas are rare fatal diseases, experience has been gathered that provides evidence for guidelines in the rational and individualized management of these diseases. For both tumors, surgery is the mainstay of treatment and can be performed with curative intention in a considerable number of patients. Patients should also be re-evaluated for curative or palliative surgery at any stage of the disease. Surgical resection or tumor mass reduction seems to improve the efficacy of adjuvant therapies and may even improve survival.
Very helpful and well-documented therapeutic agents are mitotane for adrenocortical carcinomas and 131I- MIBG for malignant pheochromocytomas. Thus, pa- tients with adrenocortical carcinoma should be routinely treated with mitotane, as 131I-MIBG is recommended for all patients with a questionable radical resection of malignant pheochromocytoma. Owing to the low inci- dence and heterogeneity of these diseases, efficacy of the advocated therapeutic regimens has not been tested in randomized, controlled trials, but experience in larger
patient series support the routine use of mitotane or 131]- MIBG, respectively.
For irresponsive disease with advanced tumor stage, cytotoxic chemotherapy regimens have been advocated. The impact on survival and quality of life is, however, less well documented with these protocols. External radiation, finally, is confined to therapy of local symptoms and bone metastases, as specific hormone antagonists and hor- mone-synthesis inhibitors are only used when other treatment modalities fail to control excessive hormone production. National and international collaboration is necessary to answer current questions on the treatment of these rare diseases and to initiate study protocols.
References
Angeli A, Osella G, Ali A, Terzolo M (1997) Adrenal incidenta- loma: an overview of clinical and epidemiological data from the National Italian Study Group. Horm Res 47: 279-283
Arlt W, Reincke M, Siekmann L, Winkelmann W, Allolio B (1994) Suramin in adrenocortical cancer: limited efficacy and serious toxicity. Clin Endocrinol (Oxf) 41: 299-307
Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, Keiser HR (1988) Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109: 267-273
Bamberger CM, Else T, Bamberger AM, Frilling A, Beil FU, Allolio B, Schulte HM (1999) Telomerase activity in benign and malignant adrenal tumors. Exp Clin Endocrinol Diabetes 107: 272-275
Bellantone R, Ferrante A, Boscherini M, Lombardi CP, Crucitti P, Crucitti F, Favia G, Borrelli D, Boffi L, Capussotti L, et al (1997) Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian Na- tional Registry for Adrenal Cortical Carcinoma. Surgery 122: 1212-1218
Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L (1998) Mito- tane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer 83: 2194-2200
Bonacci R, Gigliotti A, Baudin E, Wion-Barbot N, Emy P, Bonnay M, Cailleux AF, Nakib I, Schlumberger M (1998) Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma. Reseau Comete INSERM. Br J Cancer 78: 546-549 Bornstein SR, Stratakis CA, Chrousos GP (1999) Adrenocortical tumors: recent advances in basic concepts and clinical man- agement. Ann Intern Med 130: 759-771
Bourcigaux N, Gaston V, Logie A, Bertagna X, Le Bouc Y, Gic- quel C (2000) High expression of cyclin E and G1 CDK and loss of function of p57KIP2 are involved in proliferation of malignant sporadic adrenocortical tumors. J Clin Endocrinol Metab 85: 322-330
Boven E, Vermorken JB, van Slooten H, Pinedo HM (1984) Complete response of metastasized adrenal cortical carcinoma with o,p’-DDD. Case report and literature review. Cancer 53: 26-269
Brown HM, Komorowski RA, Wilson SD, Demeure MJ, Zhu Yr (1999) Predicting metastasis of pheochromocytomas using DNA flow cytometry and immunohistochemical markers of cell proliferation: a positive correlation between MIB-1 staining and malignant tumor behavior. Cancer 86: 1583-1589
Bukowski RM, Wolfe M, Levine HS, Crawford DE, Stephens RL, Gaynor E, Harker WG (1993) Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol 11: 161-165
Chan NN, Isaacs AJ (1999) Lack of response to octreotide in Cushing’s syndrome due to metastatic adrenocortical carcino- ma. Postgrad Med J 75: 96-97
Cottin Y, Berriolo A, Guy F, Toubeau M, Belleville I, Brenot R, Brunotte F, Wolf JE (1999) Somatostatin-receptor scintigraphy identifies a cardiac pheochromocytoma. Circulation 100: 2387- 2388
Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P (1996) The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119: 161-170
Dabrowska B, Pruszczyk P, Dabrowski A, Feltynowski T, Wocial B, Januszewicz W (1995) Influence of alpha-adrenergic block- ade on ventricular arrhythmias, QTc interval and heart rate variability in phaeochromocytoma. J Hum Hypertens 9: 925- 929
de Castro F, Isa W, Aguera L, Rosell Costa D, Abad JI, Robles JE, Zudaire JJ, Berian JM (1993) Primary adrenal carcinoma. Actas Urol Esp 17: 30-34
Decker RA, Kuehner ME (1991) Adrenocortical carcinoma. Am Surg 57: 502-513
Dogliotti L, Berruti A, Pia A, Paccotti P, Ali A, Angeli A (1995) Cytotoxic chemotherapy for adrenocortical carcinoma. Miner- va Endocrinol 20: 105-109
Duerr EM, Gimm O, Neuberg DS, Kum JB, Clifford SC, Toledo SP, Maher ER, Dahia PL, Eng C (1999) Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations. J Clin Endocrinol Metab 84: 3207-3211
Duncan MW, Compton P, Lazarus L, Smythe GA (1988) Mea- surement of norepinephrine and 3,4-dihydroxyphenylglycol in urine and plasma for the diagnosis of pheochromocytoma. N Engl J Med 319: 136-142
Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR (1999) Plasma normetanephrine and meta- nephrine for detecting pheochromocytoma in von Hippel- Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 340: 1872-1879
Engelhardt D, Weber MM (1994) Therapy of Cushing’s syndrome with steroid biosynthesis inhibitors. J Steroid Biochem Mol Biol 49: 261-267
Fallo F, Pilon C, Barzon L, Pistorello M, Pagotto U, Altavilla G, Boscaro M, Sonino N (1996) Effects of taxol on the human NCI-H295 adrenocortical carcinoma cell line. Endocr Res 22: 709-715
Favia G, Lumachi F, Carraro P, D’Amico DF (1995) Adrenocor- tical carcinoma. Our experience. Minerva Endocrinol 20: 95-99 Feldman D (1986) Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis. Endocr Rev 7: 409-420
Finkenstedt G, Gasser RW, Hofle G, Lhotta K, Kolle D, Gsch- wendtner A, Janetschek G (1999) Pheochromocytoma and sub- clinical Cushing’s syndrome during pregnancy: diagnosis, medical pre-treatment and cure by laparoscopic unilateral adrenalectomy. J Endocrinol Invest 22: 551-557
Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlumberger M, Louvel A, Luton JP, Le Bouc Y (1997) Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tu- mors: study on a series of 82 tumors. J Clin Endocrinol Metab 82: 2559-2565
Goldstein RE, O’Neill JA Jr, Holcomb GW 3rd, Morgan WM 3rd, Neblett WW 3rd, Oates JA, Brown N, Nadeau J, Smith B, Page DL, et al (1999) Clinical experience over 48 years with pheo- chromocytoma. Ann Surg 229: 755-764
Goretzki PE, Simon D, Roher HD (1997) Surgical concepts in sporadic and familial pheochromocytoma. Zentralbl Chir 122: 467-472
Gortz B, Roth J, Speel EJ, Krahenmann A, De Krijger RR, Ma- tias-Guiu X, Muletta-Feurer S, Rutmann K, Saremaslani P, Heitz PU, et al (1999) MEN1 gene mutation analysis of spo- radic adrenocortical lesions. Int J Cancer 80: 373-379
Graham PE, Smythe GA, Edwards GA, Lazarus L (1993) Labo- ratory diagnosis of phaeochromocytoma: which analytes should we measure? Ann Clin Biochem 30: 129-134
Haak HR, Cornelisse CJ, Hermans J, Cobben L, Fleuren GJ (1993) Nuclear DNA content and morphological characteristics in the prognosis of adrenocortical carcinoma. Br J Cancer 68: 151-155 Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM (1994) Optimal treatment of adreno- cortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 69: 947-951
Harrison LE, Gaudin PB, Brennan MF (1999) Pathologic features of prognostic significance for adrenocortical carcinoma after curative resection. Arch Surg 134: 181-185
Hutter AM, Kayhoe DE (1965) Adrenal cortical carcinoma: clin- ical features of 138 patients. A J Med: 572-580
Ilvesmaki V, Liu J, Heikkila P, Kahri AI, Voutilainen R (1998) Expression of insulin-like growth factor binding protein 1-6 genes in adrenocortical tumors and pheochromocytomas. Horm Metab Res 30: 619-623
Jalil ND, Pattou FN, Combemale F, Chapuis Y, Henry JF, Peix JL, Proye CA (1998) Effectiveness and limits of preoperative imaging studies for the localisation of pheochromocytomas and paragangliomas: a review of 282 cases. French Association of Surgery (AFC), and The French Association of Endocrine Surgeons (AFCE). Eur J Surg 164: 23-28
James VH, Few JD (1985) Adrenocorticosteroids: chemistry, syn- thesis and disturbances in disease. Clin Endocrinol Metab 14: 867-892
James LA, Kelsey AM, Birch JM, Varley JM (1999) Highly consistent genetic alterations in childhood adrenocortical tumours detected by comparative genomic hybridization. Br J Cancer 81: 300-304 Jensen JC, Pass HI, Sindelar WF, Norton JA (1991) Recurrent or metastatic disease in select patients with adrenocortical carci- noma. Aggressive resection vs chemotherapy. Arch Surg 126: 457-461
Jirari A, Charpentier A, Popescu S, Boidin P, Eisenmann B (1999) A malignant primary cardiac pheochromocytoma. Ann Thorac Surg 68: 565-566
Kasperlik-Zaluska AA, Migdalska BM, Zgliczynski S, Makowska AM (1995) Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Cancer 75: 2587-2591
Kasperlik-Zaluska AA, Roslonowska E, Slowinska-Srzednicka J, Migdalska B, Jeske W, Makowska A, Snochowska H (1997) Incidentally discovered adrenal mass (incidentaloma): investi- gation and management of 208 patients. Clin Endocrinol (Oxf) 46: 29-37
Kolomecki K, Pomorski L, Kuzdak K, Narebski J, Wichman R (1999) The surgical treatment of adrenal gland tumors - inci- dentaloma. Neoplasma 46: 124-127
Kopf D, Bockisch A, Steinert H, Hahn K, Beyer J, Neumann HP, Hensen J, Lehnert H (1997) Octreotide scintigraphy and cate- cholamine response to an octreotide challenge in malignant phaeochromocytoma. Clin Endocrinol 46: 39-44
Krempf M, Lumbroso J, Mornex R, Brendel AJ, Wemeau JL, Delisle MJ, Aubert B, Carpentier P, Fleury-Goyon MC, Gibold C, et al (1991) Use of m-[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 72: 455-461
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stack- house T, Kuzmin I, Modi W, Geil L, et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Sci- ence 260: 1317-1320
Law A, Hague WM, Daly JG, Honour JW, Taylor N, Jeffcoate SL, Himsworth RL, Joplin GF (1988) Inappropriate ACTH con- centrations in two patients with functioning adrenocortical carcinoma. Clin Endocrinol 29: 53-62
Lee JE, Berger DH, el-Naggar AK, Hickey RC, Vassilopoulou- Sellin R, Gagel RF, Burgess MA, Evans DB (1995) Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118: 1090-1098
Lehnert H (1995) Diagnostik und Therapie des malignen Phäo- chromozytoms. In: Lehnert H, Kopf D, Hensen J (eds) En- dokrine Tumoren: Prognostische Parameter, rationelle Diagnostik und Therapie. Bundesdruckerei, Berlin, pp 157-165
Lehnert H, Schulz C, Mundschenk J, Kopf D (1997) Clinical and endocrine diagnosis of pheochromocytoma. Zentralbl Chir 122: 447-453
Lehnert H (1998) Regulation of catecholamine synthesizing enzyme gene expression in human pheochromocytoma. Eur J Endo- crinol 138: 363-367
Lenders JW, Keiser HR, Goldstein DS, Willemsen JJ, Friberg P, Jacobs MC, Kloppenborg PW, Thien T, Eisenhofer G (1995) Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 123: 101-109
Letizia C, De Toma G, Massa R, Corsi A, Caliumi C, Subioli S, D’Erasmo E (1998) False-positive diagnosis of adrenal pheo- chromocytoma on iodine-123-MIBG scan. J Endocrinol Invest 21: 779-783
Lin SR, Yang YC, Tsai JH, Hsu CH (1998) Alterations of RET oncogene in human adrenal tumors. Jpn J Cancer Res 89: 634- 640
Logie A, Boulle N, Gaston V, Perin L, Boudou P, Le Bouc Y, Gicquel C (1999) Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. J Mol Endocrinol 23: 23-32
Loh KC, Fitzgerald PA, Matthay KK, Yeo PP, Price DC (1997) The treatment of malignant pheochromocytoma with iodine- 131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest 20: 648- 658
Lu X, Stallmach T, Gebbers JO (1996) Image cytometric DNA analysis of adrenocortical neoplasms as a prognostic parameter: a clinico-pathologic study of 13 patients. Anal Cell Pathol 12: 1-11
Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouv- erture M, Simon D, Laudat MH, Touitou Y, Bricaire H (1979) Treatment of Cushing’s disease by O,p’DDD. Survey of 62 cases. N Engl J Med 300: 459-464
Luton JP, Cerdas S, Billaud L, Thomas G, Guilhaume B, Bertagna X, Laudat MH, Louvel A, Chapuis Y, Blondeau P, et al (1990) Clinical features of adrenocortical carcinoma, prognostic fac- tors, and the effect of mitotane therapy. N Engl J Med 322: 1195-1201
MacFarlaine DA (1958) Cancer of the adrenal cortex: the natural history, prognosis and treatment in a study of fifty-five cases. Ann R Coll Surg Engl 23: 155-186
Magee BJ, Gattamaneni HR, Pearson D (1987) Adrenal cortical carcinoma: survival after radiotherapy. Clin Radiol 38: 587-588 Mancini F, Mutter D, Peix JL, Chapuis Y, Henry JF, Proye C, Cougard P, Marescaux J (1999) Experiences with adrenalecto- my in 1997. Apropos of 247 cases. A multicenter prospective study of the French-speaking Association of Endocrine Sur- gery. Chirurgie 124: 368-374
Manger T, Piatek S, Klose S, Kopf D, Kunz D, Lehnert H, Lippert H (1997) Bilateral laparoscopic transperitoneal adrenalectomy in pheochromocytoma. Langenbecks Arch Chir 382: 37-42
Markoe AM, Serber W, Micaily B, Brady LW (1991) Radiation therapy for adjunctive treatment of adrenal cortical carcinoma. Am J Clin Oncol 14: 170-174
McLeod MK, Thompson NW, Gross MD, Bondeson AG, Bondeson L (1990) Sub-clinical Cushing’s syndrome in patients with adrenal gland incidentalomas. Pitfalls in diagnosis and management. Am Surg 56: 398-403
McNicol AM, Nolan CE, Struthers AJ, Farquharson MA, Hermans J, Haak HR (1997) Expression of p53 in adrenocor- tical tumours: clinicopathological correlations. J Pathol 181: 146-152
Meco D, Lasorella A, Riccardi A, Servidei T, Mastrangelo R, Riccardi R (1999) Influence of cisplatin and doxorubicin on 125I-meta-iodobenzylguanidine uptake in human neuroblas- toma cell lines. Eur J Cancer 35: 1227-1234
Miller JW, Crapo L (1993) The medical treatment of Cushing’s syndrome. Endocr Rev 14: 443-458
Mornex R, Badet C, Peyrin L (1992) Malignant pheochromocy- toma: a series of 14 cases observed between 1966 and 1990. J Endocrinol Invest 15: 643-649
Mulligan LM, Timmer T, Ivanchuk SM, Campling BG, Young LC, Rabbitts PH, Sundaresan V, Hofstra RM, Eng C (1998) Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-I, in small cell lung carcinoma. Genes Chromosomes Cancer 21: 326-332
Mundschenk J, Lehnert H (1998a) Malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 106: 373-376
Mundschenk J, Kopf D, Lehnert H (1998b) Therapy of malignant pheochromocytoma. Invitation to participate in a randomized multicenter study (letter). Dtsch Med Wochenschr 123: 32-33
Mundschenk J, Schulz S, Höllt V, Lehnert H (2000) Immuno- cytochemical evidence for somatostatin receptor subtype SST3 in malignant pheochromocytoma. Exp Clin Endocrinol Dia- betes 108 (Suppl. 1): 147
National Cancer Institute, Biometrics branch (1975) In: Cutler SJ, Young JL (eds) Third National Cancer Survey: incidence data. National Cancer Institute Monograph 41. Government Printing Office, Washington, D.C., (DHEW publication no. (NIH) 75- 787)
Neumann HP, Reincke M, Bender BU, Elsner R, Janetschek G (1999) Preserved adrenocortical function after laparoscopic bilateral adrenal sparing surgery for hereditary pheochromo- cytoma. J Clin Endocrinol Metab 84: 2608-2610
Newhouse JH, Heffess CS, Wagner BJ, Imray TJ, Adair CF, Davidson AJ (1999) Large degenerated adrenal adenomas: ra- diologic-pathologic correlation. Radiology 210: 385-391
Oishi S, Sato T (1988) Elevated serum neuron-specific enolase in patients with malignant pheochromocytoma. Cancer 61: 1167- 1170
Orchard T, Grant CS, van Heerden JA, Weaver A (1993) Pheo- chromocytoma: continuing evolution of surgical therapy. Surgery 114: 1153-1158
Pasieka JL, McLeod MK, Thompson NW, Gross MD, Schteingart DE (1992) Adrenal scintigraphy of well-differentiated (func- tioning) adrenocortical carcinomas: potential surgical pitfalls. Surgery 112: 884-890
Peaston RT, Lennard TW, Lai LC (1996) Overnight excretion of urinary catecholamines and metabolites in the detection of pheochromocytoma. J Clin Endocrinol Metab 81: 1378-1384 Pittasch D, Klose S, Schmidt J, Roessner A, Ridwelski K, Lippert H, Lehnert H (2000) Retroperitoneal schwannoma presenting as an adrenal tumor. A case report. Exp Clin Endocrinol Dia- betes 108: 318-321
Plouin PF, Chatellier G, Fofol I, Corvol P (1997) Tumor recur- rence and hypertension persistence after successful pheo- chromocytoma operation. Hypertension 29: 1133-1139
Pommier RF, Brennan MF (1992) An eleven-year experience with adrenocortical carcinoma. Surgery 112: 963-970
Proye C, Thevenin D, Cecat P, Petillot P, Carnaille B, Verin P, Sautier M, Racadot N (1989) Exclusive use of calcium channel blockers in preoperative and intraoperative control of pheo- chromocytomas: hemodynamics and free catecholamine assays in ten consecutive patients. Surgery Dec 106: 1149-1154
Proye C, Vix M, Goropoulos A, Kerlo P, Lecomte-Houcke M (1992) High incidence of malignant pheochromocytoma in a surgical unit. 26 cases out of 100 patients operated from 1971 to 1991. J Endocrinol Invest 15: 651-663
Proye CA, Vix M, Jansson S, Tisell LE, Dralle H, Hiller W (1994) “The” pheochromocytoma: a benign, intra-adrenal, hyperten- sive, sporadic unilateral tumor. Does it exist? World J Surg 18: 467-472
Proye C, Jafari Manjili M, Combemale F, Pattou F, Ernst O, Carnaille B, Wemeau JL (1998) Experience gained from oper- ation of 103 adrenal incidentalomas. Langenbecks Arch Surg 383: 330-333
Quarles Van Ufford-Mannesse P, Castro Cabezas M, Vroom TM, Van Gils A, Lips CJ, Niermeijer P (1999) A patient with neu- rofibromatosis type 1 and watery diarrhoea syndrome due to a VIP-producing adrenal phaeochromocytoma. J Intern Med 246: 231-234
Reincke M, Karl M, Travis WH, Mastorakos G, Allolio B, Line- han HM, Chrousos GP (1994) p53 mutations in human
adrenocortical neoplasms: immunohistochemical and molecular studies. J Clin Endocrinol Metab 78: 790-794
Reubi JC, Waser B, Khosla S, Kvols L, Goellner JR, Krenning E, Lamberts S (1992) In vitro and in vivo detection of somatost- atin receptors in pheochromocytomas and paragangliomas. J Clin Endocrinol Metab 74: 1082-1089
Ross GA, Newbould EC, Thomas J, Bouloux PM, Besser GM, Perrett D, Grossman A (1993) Plasma and 24 h-urinary cate- cholamine concentrations in normal and patient populations. Ann Clin Biochem 30: 38-44
Russell WJ, Metcalfe IR, Tonkin AL, Frewin DB (1998) The preoperative management of phaeochromocytoma. Anaesth Intensive Care 26: 196-200
Sameshima Y, Tsunematsu Y, Watanabe S, Tsukamoto T, Kawa-ha K, Hirata Y, Mizoguchi H, Sugimura T, Terada M, Yokota J (1992) Detection of novel germ-line p53 mutations in diverse- cancer-prone families identified by selecting patients with child- hood adrenocortical carcinoma. J Natl Cancer Inst 84: 703-707 Sasano H, Shizawa S, Nagura H (1995) Adrenocortical cytopa- thology. Am J Clin Pathol 104: 161-166
Schlumberger M, Gicquel C, Lumbroso J, Tenenbaum F, Comoy E, Bosq J, Fonseca E, Ghillani PP, Aubert B, Travagli JP, et al (1992) Malignant pheochromocytoma: clinical, biological, his- tologic and therapeutic data in a series of 20 patients with distant metastases. J Endocrinol Invest 15: 631-642
Schlund JF, Kenney PJ, Brown ED, Ascher SM, Brown JJ, Sem- elka RC (1995) Adrenocortical carcinoma: MR imaging appearance with current techniques. J Magn Reson Imaging 5: 171-174
Schulick RD, Brennan MF (1999) Long-term survival after com- plete resection and repeat resection in patients with adreno- cortical carcinoma. Ann Surg Oncol 6: 719-726
Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC (1999) Pheochromocytomas: imaging with 2-[fluorine-18]fluoro- 2-deoxy-D-glucose PET. Radiology 212: 35-41
Sisson JC, Shapiro B, Beierwaltes WH, Glowniak JV, Nakajo M, Mangner TJ, Carey JE, Swanson DP, Copp JE, Satterlee WG, et al (1984) Radiopharmaceutical treatment of malignant pheochromocytoma. J Nucl Med 25: 197-206
Sisson JC, Shapiro B, Shulkin BL, Urba S, Zempel S, Spaulding S (1999a) Treatment of malignant pheochromocytomas with 131- I metaiodobenzylguanidine and chemotherapy. Am J Clin Oncol 22: 364-370
Sisson JC, Shulkin BL (1999b) Nuclear medicine imaging of pheochromocytoma and neuroblastoma. Q J Nucl Med 43: 217-223
Sjoberg RJ, Simcic KJ, Kidd GS (1992) The clonidine suppression test for pheochromocytoma. A review of its utility and pitfalls. Arch Intern Med 152: 1193-1197
Steinsapir J, Carr AA, Prisant LM, Bransome ED Jr (1997) Metyrosine and pheochromocytoma. Arch Intern Med 157: 901-906
Stridsberg M, Husebye ES (1997) Chromogranin A and chro- mogranin B are sensitive circulating markers for phaeochrom- ocytoma. Eur J Endocrinol 136: 67-73
Sullivan M, Boileau M, Hodges CV (1978) Adrenal cortical car- cinoma. J Urol 120: 660-665
Szolar DH, Unger B, Heinz-Peer G, Preidler K, Ranner G (1999) Differential diagnosis of space-occupying adrenal masses. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 171: 269-278
Tanaka S, Ito T, Tomoda J, Higashi T, Yamada G, Tsuji T (1993) Malignant pheochromocytoma with hepatic metastasis diag-
nosed 20 years after resection of the primary adrenal lesion. Intern Med 32: 789-794
Tenenbaum F, Lumbroso J, Schlumberger M, Mure A, Plouin PF, Caillou B, Parmentier C (1995) Comparison of radiolabeled octreotide and meta-iodobenzylguanidine (MIBG) scintigraphy in malignant pheochromocytoma. J Nucl Med 36: 1-6
Terzolo M, Ali A, Osella G, Mazza E (1997) Prevalence of adrenal carcinoma among incidentally discovered adrenal masses. A retrospective study from 1989 to 1994. Gruppo Piemontese Incidentalomi Surrenalici. Arch Surg 132: 914-919
Thoren M, Adamson U, Sjoberg HE (1985) Aminoglutethimide and metyrapone in the management of Cushing’s syndrome. Acta Endocrinol (Copenh) 109: 451-457
Troncone L, Rufini V (1999) Nuclear medicine therapy of pheo- chromocytoma and paraganglioma. Q J Nucl Med 43: 344 355
Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC (1999) Suc- cessful outcomes in pheochromocytoma surgery in the modern era. J Urol 161: 764-767
Vargas MP, Zhuang Z, Wang C, Vortmeyer A, Linehan WM, Merino MJ (1997) Loss of heterozygosity on the short arm of chromosomes 1 and 3 in sporadic pheochromocytoma and extra-adrenal paraganglioma. Hum Pathol 28: 411-415
Vassilopoulou-Sellin R, Guinee VF, Klein MJ, Taylor SH, Hess KR, Schultz PN, Samaan NA (1993) Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71: 3119-3123
Villa R, Orlandi L, Berruti A, Dogliotti L, Zaffaroni N (1999) Modulation of cytotoxic drug activity by mitotane and lonid- amine in human adrenocortical carcinoma cells. Int J Oncol 14: 133-138
Voutilainen R (1998) Adrenocortical cells are the site of secretion and action of insulin-like growth factors and TNF-x. Horm Metab Res 30: 432-435
Wagner J, Portwine C, Rabin K, Leclerc JM, Narod SA, Malkin D (1994) High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst 86: 1707-1710
Walther MM, Keiser HR, Linehan WM (1999) Pheochromocy- toma: evaluation, diagnosis, and treatment. World J Urol 17: 35-39
Woodward ER, Eng C, McMahon R, Voutilainen R, Affara NA, Ponder BA, Maher ER (1997) Genetic predisposition to phae- ochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet 6: 1051-1056
Wooten MD, King DK (1993) Adrenal cortical carcinoma. Epi- demiology and treatment with mitotane and a review of the literature. Cancer 72: 3145-3155
Wu HC, Shih LY, Chen TC, Chu SH, Tsai CC (1999) A patient with bilateral primary adrenal lymphoma, presenting with fever of unknown origin and achieving long-term disease-free sur- vival after resection and chemotherapy. Ann Hematol 78: 289- 292
Yoshimoto T, Naruse M, Zeng Z, Nishikawa T, Kasajima T, Toma H, Yamamori S, Matsumoto H, Tanabe A, Naruse K, et al (1998) The relatively high frequency of p53 gene mutations in multiple and malignant phaeochromocytomas. J Endocrinol 159: 247-255
Zhao J, Speel EJ, Muletta-Feurer S, Rutimann K, Saremaslani P, Roth J, Heitz PU, Komminoth P (1999) Analysis of genomic alterations in sporadic adrenocortical lesions. Gain of chro- mosome 17 is an early event in adrenocortical tumorigenesis. Am J Pathol 155: 1039-1045