Surgical therapy of adrenal tumors: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: Previous guidelines addressing surgery of adrenal tumors required actualization in adaption of developments in the area. The present guideline aims to provide practical and qualified recommendations on an evidence-based level reviewing the prevalent literature for the surgical therapy of adrenal tumors referring to patients of all age groups in operative medicine who require adrenal surgery. It primarily addresses general and visceral surgeons but offers information for all medical doctors related to conservative, ambulatory or inpatient care, rehabilitation, and general practice as well as pediatrics. It extends to interested patients to improve the knowledge and participation in the decision-making process regarding indications and methods of management of adrenal tumors. Furthermore, it provides effective medical options for the surgical treatment of adrenal lesions and balances positive and negative effects. Specific clinical questions addressed refer to indication, diagnostic procedures, effective therapeutic alternatives to surgery, type and extent of surgery, and postoperative management and follow-up regime. METHODS: A PubMed research using specific key words identified literature to be considered and was evaluated for evidence previous to a formal Delphi decision process that finalized consented recommendations in a multidisciplinary setting. RESULTS: Overall, 12 general and 52 specific recommendations regarding surgery for adrenal tumors were generated and complementary comments provided. CONCLUSION: Effective and balanced medical options for the surgical treatment of adrenal tumors are provided on evidence-base. Specific clinical questions regarding indication, diagnostic procedures, alternatives to and type as well as extent of surgery for adrenal tumors including postoperative management are addressed.

[Neuroendocrine neoplasms of the distal jejunum and ileum]. / Neuroendokrine Neoplasien des distalen Jejunums und Ileums.

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.

[Neuroendocrine tumours of the GI tract--data from the German NET Registry]. / Neuroendokrine Tumoren des Verdauungstrakts - Daten des deutschen NET-Registers.

BACKGROUND: Neuroendocrine tumours (NET) are rare and heterogeneous neoplasia. To obtain valid data on epidemiology, diagnostics, therapy, prognosis and risk factors is the aim of the German NET registry. PATIENTS AND METHODS: Data from 2009 histologically proven NET were collected from 35 NET centres between 1999 and 2010. Data collection has been performed prospectively since 2004. Results: Median follow-up was 34.5 months and median age at diagnosis 56.4 years. Primary tumour localisations were pancreas (34.2%), midgut (5.8%), stomach (6.5%), bowel (6.9%), duodenum (4.8%) and neuroendocrine CUP (12.6%). Synchronous metastases were seen in 46% and second malignancies in 12%. From 860 patients, 402 (46.7%) had functional tumours with the following hormone excess syndromes: carcinoid syndrome (19.1%; n = 164), persistent hyperinsulinaemic hypoglycaemia (17.7%; n = 152), Zollinger- Ellison syndrome (7.1%; n = 61), glucagonoma (0.7%; n = 15), Verner-Morrison syndrome (0.4%; n = 8) and somatostatinoma syndrome(0.1%; n = 2). Surgical therapy was performed in 78%, therapy with somatostatin receptor analogues(SSA) in 28%, peptide radioreceptor therapy (PRRT) in 19%, chemotherapy in 18% and interferon therapy in 6.5%. Only surgery was done in 47%, whereas 53% received a second therapy. General mortality rate during follow-up was 14.9%. The tumour-specific survival rates for 2, 5 and 10 years were 94, 85 and 70%. The 5-year survival is dependent on the surgical or non-surgical therapy (82 versus 61%, p < 0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p < 0.001). Grading (G1, G2, G3) based on proliferation index Ki-67 recommended by the ENETS guidelines and WHO classification is highly correlated to the 5-year survival rate (88, 82, 33%, p < 0.001). CONCLUSION: The German NET registry provides valid multicentric data on NET in Germany. Surgical therapy is the most frequent and important therapy with good clinical outcome. In non-resectable, metastatic tumours, systemic therapies are common. Continuation and evaluation of the new WHO and TNM classifications for NET and their therapies will be a future focus of the registry.

[Surgical therapy for thyroid gland malignancies]. / Chirurgie der Schilddrüsenmalignome.

Surgical therapy for thyroid neoplasms is based on tumor histology and comprises stage-adapted procedures with a high degree of inter-individual variability. This can range from waiting and monitoring, to extensive multivisceral surgery. Grouping together histologically different types of malignancies leads to false assumptions when gauging the radicality of surgery necessary in each particular case. Surgical therapy requires not only an understanding of the biological behavior of the tumor and the risk that it or the therapy poses to the patient, but also knowledge of a wide surgical spectrum of limited and complex resection procedures in the neck and thorax region. The following recommendations are based primarily on the guidelines of the Surgical Working Group for Endocrinology of the German Society for General and Visceral Surgery as well as on the authors' own experience and, where indicated, the guidelines of other working groups.

[Surgery for neuroendocrine tumors of the gastroenteropancreatic system (GEP-NET)]. / Chirurgie neuroendokriner Tumoren des gastroenteropankreatischen Systems (GEP-NET).

Surgical treatment is still the only curative treatment proven for patients with neuroendocrine tumors (NET) of the gastroenteropancreatic system. In addition to the therapy of incidental findings, the treatment of NET with variable aggressiveness and often good long-term prognosis requires a thorough preoperative assessment and a surgical procedure that is based on each individual case. Treatment can be surgery alone (if the disease is locally confined) or can be combined with other therapies. Early NET of the stomach and rectum can be cured endoscopically without further diagnostics, while early findings of the appendix can be treated by an appendectomy. Functionally active pancreatic NET and NET of the small intestine are often preoperatively diagnosed based on symptoms. Thus, it is possible to refer the patient to a NET center, if necessary. Stratification of the necessary treatment combination can be made early. An alternative to radical surgical treatment is the operative reduction of the tumor size and hormone production in metastasized NET, which can lead to improved life expectancy and quality of life. Combination with other treatment forms is absolutely necessary in these patients. It has been proven useful to divide the large group of NET based on the different tumor locations, hormone activity, and the degree of differentiation of the tumor. Early forms, locoregionally limited tumor stages, and tumor stages with distant metastases are considered separately.

[Pancreatic hyperinsulinism--changes of the clinical picture and importance of differences in sporadic disease course (experience with 144 patients operated in the period 1986-2009)]. / Pankreatischer Hyperinsulinismus--Wandel des Krankheitsbildes mit spezifischen Unterschieden auch bei sporadischen Erkrankungsformen (Eigene Erfahrung an 144 operierten Patienten von 1986-2009).

The diagnoses of pancreatogenic hyperinsulinism and insulinoma (benign or malignant) were almost synonomously used during the last decades. Only familial forms of hyperinsulinism, i. e., in patients with multiple endocrine neoplasia type 1 were separately discussed. The surgical literature concentrated on technical questions, comparing open and minimal invasive techniques. The clinical diagnosis of patients with pancreatogenic hypo-glycaemia syndrome (NIPHS) and the pathological diagnosis of insulinomatosis has now opened up new questions in the diagnosis and therapy of pancreatogenic hyperinsulinism. On the basis of our experience from 144 patients operated on for pancreatogenic hyperinsulinism during the last 22 years with 16 NIPHS patients and with the help of the relevant literature, we explain the prerequisites that surgical therapy has to fulfil in the treatment of patients with pancreatogenic hyperinsulinism today.

Nestin as a marker in the classification of adrenocortical tumors.

Expression of the intermediate filament, nestin, was long believed to be restricted to neuroectodermal stem cells. However, nestin expression has recently been detected in several tumors. Since adrenocortical carcinoma, a tumor entity still very difficult to classify, may gain the ability to aberrantly express neuroectodermal proteins including chromogranin A and synaptophysin, we asked the question whether nestin might also be detected in adrenocortical carcinomas, and if so, whether it might serve as a tool for clinical pathology. Therefore, we studied the expression of nestin in normal adrenal glands, adrenocortical adenomas, and adrenocortical cancers using specific immunohistochemistry and semi-quantitative reverse transcriptase-polymerase chain reaction. Immunostaining was nestin-positive in 1 out of 9 normal adrenal glands (11%), 2 out of 20 adrenocortical adenomas (10%), and 13 out of 16 adrenocortical carcinomas (81%). Expression of nestin mRNA could be detected in all microdissected tissues, independently of their grade of dedifferentiation. We conclude that our findings provide further evidence that nestin, as a marker, is not restricted to neuronal stem cells and nestin expression is worth to be studied in adrenocortical tumors.

Presentation of 6 cases with parathyroid cysts and discussion of the literature.

INTRODUCTION: Cystic lesions of the parathyroid glands are uncommon, and rare are those that cause primary hyperparathyroidism. Preoperative diagnosis can be challenging and some of these tumors might be misinterpreted as parathyroid carcinoma. With an expertise of more than 1700 patients operated on primary hyperparathyroidism, we present six cases with cystic degeneration of a parathyroid gland causing primary hyperparathyroidism in five patients. CASE REPORTS: A woman at the age of 67 presented with hypercalcaemic crisis due to persistent primary hyperparathyroidism after an operation four years ago. As cervical exploration was unsuccessful, sternotomy was performed and a cystic adenoma of a parathyroid gland could be resected from the anterior mediastinum. The second patient - a 63-year-old female with severe hypercalcaemic crisis, operated on under suspicion of a parathyroid carcinoma - had a functional cyst of the parathyroid gland with a parathyroid hormone level of 700,000 pg/ml in the aspirated fluid. Third, operation on a 70-year-old woman with a benign euthyreot goiter and the laboratory findings of primary hyperparathyroidism revealed a cystic adenoma adjacent to the thyroid gland, whose aspirate had a parathyroid hormone level of 1,500,000 pg/ml. In the fourth case of a 67-year-old female with an adenoma of the right inferior parathyroid gland localized by ultrasonography, the cystic parathyroid adenoma was operated on by video-assistance. A cystic structure in the upper mediastinum was diagnosed in the fifth patient, a 66-year-old woman. It was suspected to be a thyroid cyst at the left-lower pole of the thyroid gland. After hemithyroidectomy pathological evaluation revealed a large parathyroid cyst. The last case of a 56-year-old male illustrates the extensive preoperative work-up of a patient with primary hyperparathyroidism who was preoperatively diagnosed as having a thyroid cyst. Final histopathological examination exposed multiple gland disease with a parathyroid adenoma as well as a cystic parathyroid gland. DISCUSSION: Cystic adenomas of the parathyroid glands are often misdiagnosed as thyroid cysts or - in the case of extremely elevated parathyroid hormone levels - even as parathyroid carcinoma. The routine preoperative diagnostic tools, such as ultrasonography or (99m)Tc-sestamibi-scintigraphy, cannot clearly distinguish between these entities and might be jeopardized by mediastinal localization, which is not uncommon in parathyroid adenomas with cystic degeneration.

[Routine measurement of serum calcitonin in patients with nodular thyroid disorders?]. / Calcitonin-Screening bei der Knotenstruma?

In spite of the fact that the German Society of Endocrinology has recommended calcitonin as screening-parameter the majority of physicians in Germany do not routinely use calcitonin in patients with thyroid nodules to exclude medullary thyroid cancer (MTC). The future revision of the recommendation should describe reference values for each commercially available assay, separately for men and women (basal and after pentagastrin-stimulation), and should define sonomorphological inclusion criteria. The epidemiological database of the prevalence of MTC is controversial and the specificity of basal elevated calcitonin levels is limited up to the 5-fold of the upper reference level. If renal insufficiency, bacterial infection, and an alcohol- or drug-induced stimulation of calcitonin is excluded, hypercalcitoninaemia should be confirmed by a second measurement (if necessary using another assay). Stimulation of calcitonin by use of pentagastrin is mandatory prior to the decision on thyroidectomy. A stimulated calcitonin level < 100 pg/ml justifies "wait and see". If stimulated calcitonin levels range between 100 and 200 pg/ml or higher, the differentiation between C-cell hyperplasia and MTC remains uncertain, especially in men. The implementation of calcitonin-screening requires the definition of sonographic inclusion criteria and validation of each assay. Additional pre-requisites are excellent logistic (short period between blood sampling and start of the laboratory test), knowledge of differential diagnoses, knowledge of the consumption of drugs and alcohol, availability of pentagastrin-testing and of moleculargenetic testing with full information to the patients and sufficient time before the decision on surgery is made. All this and the choice of a skilled surgeon, experienced in thyroidectomy and lymphadenectomy with a low rate of local complications are the rationale to recommend calcitonin-screening primarily in centers for thyroid disorders.

[Abdominal preoperation. No contraindication for laparoscopic transabdominal adrenalectomy]. / Abdominelle Voroperationen. Keine Kontraindikation für eine laparoskopische transabdominelle Adrenalektomie.

Benign adrenal gland tumors smaller than 6 cm are nowadays the indication for minimally invasive surgery. Until now there has been no significant difference between retroperitoneoscopic and transabdominal adrenalectomy. Intestinal adhesions could be a contraindication against transabdominal laparoscopic adrenalectomy, and therefore the retroperitoneoscopic approach could be an advantage in these cases. A prospective study concerning this question has not been published yet. Our clinical investigation here includes 114 adrenalectomies during the last 5 years. We show that in any case of abdominal preoperation, laparoscopic adrenalectomy can be performed by transabdominal approach and without conversion to open surgery. Discussed are the different indications for laparoscopic adrenalectomy, operating time, conversion rate to open surgery, and amount and type of abdominal preoperation. We compared patients with and without abdominal preoperations.

[Update of the S2k guidelines : Surgical treatment of benign thyroid diseases]. / Aktualisierung der S2k-Leitlinie : Operative Therapie benigner Schilddrüsenerkrankungen.

Thyroid resections represent one of the most common operations with 76,140 interventions in the year 2016 in Germany (source Destatis). These are predominantly benign thyroid gland diseases. Recommendations for the operative treatment of benign thyroid diseases were last published by the CAEK in 2010 as S2k guidelines (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. [AWMF] 003/002) against the background of increasingly more radical resection procedures. Hemithyroidectomy and thyroidectomy are routinely performed for benign thyroid disease in practice. The operation-specific risks show a clear increase with the extent of the resection. Therefore, weighing-up of the risk-indications ratio between unilateral lobectomy or thyroidectomy necessitates an independent evaluation of the indications for both sides. This principle in particular has been used to update the guidelines. In addition, the previously published recommendations of the CAEK for correct execution and consequences of intraoperative neuromonitoring were included into the guidelines, which in particular serve the aim to avoid bilateral recurrent laryngeal nerve paralysis. Moreover, the recommendations for the treatment of postoperative complications, such as hypoparathyroidism and postoperative infections were revised. The updated guidelines therefore represent the current state of the science as well as the resulting surgical practice.

Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

Mutation of the p53 gene in a differentiated human thyroid carcinoma cell line, but not in primary thyroid tumours.

The p53 gene has been implicated as a tumour suppressor, with mutations occurring in many carcinomas, such as colon, breast and lung. We have sequenced exons 5, 7 and 8 containing conserved gene regions in the only available differentiated thyroid follicular carcinoma cell line and found a mutation at position 273, Arg----His, with no normal allele present. The same mutation was also present in DNA from the tumour of origin. However immunohistochemical analysis of 129 human thyroid tumours using a panel of p53 antibodies was unequivocally negative. Southern blotting in 20 cases failed to demonstrate any deletion or rearrangement, and direct genomic sequencing of 20 carcinomas showed normal DNA sequence for exons 5, 7 and 8. Thus p53 abnormalities may not be important in human thyroid carcinogenesis, in contrast to colon, breast and lung. However, the FTC 133 cell line was only established after 132 unsuccessful attempts with other differentiated thyroid follicular tumours. Since this line and the corresponding tumour of origin have a p53 mutation, we propose that p53 mutation may confer on thyroid follicular tumour cells the ability to grow in culture. This has potential applications for the future development of thyroid carcinoma cell lines.

[New aspects in hernia surgery]. / Aktuelle Aspekte der Hernienchirurgie.

In the last 10 years in Germany we have seen a lot of hernia repairs using mesh.Meta-analysis shows the advantages of using meshes in hernia surgery; recurrence rates in inguinal hernia surgery are less than 3% in studies. There is some discussion about minimally invasive surgery in Germany.In incisional hernia surgery there is no discussion about using meshes. The role of minimally invasive surgery has not yet been defined.

Characterization of the thyrotropin receptor-adenylate cyclase system in neoplastic human thyroid tissue.

Experiments were performed to determine whether the TSH receptor-adenylate cyclase (AC) system in benign and malignant thyroid neoplasms differs from the TSH receptor-AC system in normal thyroid tissue removed from the same patients. TSH binding and AC assays were performed using the same in vitro conditions. TSH binding was rapid, reversible, saturable, and hormone specific in particulate fractions from both normal and neoplastic thyroid tissue. A positive correlation existed between the equilibrium constants for [125I]bovine ([125I]bTSH) TSH binding and the concentration of TSH required to activate AC, suggesting that binding sites were coupled to AC in neoplastic thyroid tissue. Mean values for dissociation constants (Kd1 and Kd2), capacity (site 2), as determined by Scatchard analysis, and nonspecific binding (NSB) for the TSH receptors were lower in neoplastic thyroid. Some normal thyroid tissue appeared to lack a high affinity site, and some tumors lacked a low affinity binding site. Hormone specificities (bTSH, human (h) TSH, hLH, hFSH, hGH, hACTH, and glucagon) in normal thyroid and neoplastic tissue were virtually identical. hFSH, hACTH, hGH, and glucagon failed to inhibit [125I]bTSH binding or stimulate AC in either normal or neoplastic thyroid tissue, whereas hLH inhibited [125I]bTSH binding and stimulated AC, but required 10- to 100-fold higher concentrations than hTSH or bTSH. The specific binding and NSB of [125I]bTSH in both normal and neoplastic thyroid tissue was highest at pH 7.0 and lowest at pH 8.3. In contrast to bTSH binding, TSH stimulation of AC was lowest at pH 7.0 in both normal and neoplastic tissues and highest at pH levels of 7.5-8.0. TSH binding and TSH stimulation of AC activity were highest in the absence of NaCl and decreased progressively as the salt concentration was increased in both normal and neoplastic thyroid tissues. Increasing the sucrose concentration and, thus, the osmolarity of the system had a minimal effect on the binding of [125I]bTSH. Preincubation with ammonium sulfate did not significantly influence binding. Basal AC activity and the AC response to TSH were greater in neoplastic thyroid than in normal tissues. These studies demonstrate that changes in salt concentration and pH affect the TSH receptor-cyclase system in a comparable fashion in normal and neoplastic thyroid tissues. The discriminatory properties of the TSH receptor are also maintained in thyroid neoplasms. Thyroid tumors, however, have a higher affinity for TSH and display a greater AC response to TSH than normal thyroid tissue.

Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

In Hashimoto's thyroiditis, Fas-induced apoptosis is one of the mechanisms leading to cell destruction, whereas thyroid tissue in Graves' disease is prevented from it. The soluble form of the Fas molecule produced by alternative splicing prevents from apoptosis. We measured soluble Fas in the sera of 112 patients with Graves' disease, 21 patients with toxic goiter, and 24 patients with subclinical hyperthyroidism due to suppressive therapy with levothyroxine after near-total resection of the thyroid gland for nodular goiter. Soluble Fas was increased in thyrotoxic patients, toxic goiter, and patients with subclinical hyperthyroidism. Decreased levels of soluble Fas were found in euthyroid patients with Graves' disease after surgery, whereas soluble Fas was normal in euthyroid patients with Graves' disease receiving antithyroid drug treatment and in patients in stable remission. There was a good correlation between soluble Fas with free T(3) (r = 0.6) and free T(4) (r = 0.5). Our results show that soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

Allelic loss of the retinoblastoma tumor suppressor gene: a marker for aggressive parathyroid tumors?

Allelic loss of the retinoblastoma tumor suppressor gene has recently been shown to be highly specific for parathyroid carcinoma. It has been proposed that this genetic abnormality may have diagnostic and prognostic implications for parathyroid carcinoma, but to date no further studies are available to substantiate these findings. In the present study, three cases of atypical recurrent hyperparathyroidism were examined: a patient with parathyroid carcinoma and an autotransplanted adenoma that progressed into carcinoma, a patient with recurrent juvenile hyperparathyroidism, and a patient with severe recurrent secondary hyperparathyroid disease due to rapidly growing autotransplant. Six pairs each of sporadic parathyroid adenoma and secondary parathyroid disease were also studied for comparison. Allelic losses of RB and D13S71 at 13q14 was found in the parathyroid carcinoma and the corresponding autotransplant that had previously been considered benign tissue and in the case of recurrent juvenile hyperparathyroidism, but not in any of the other tumors. Our findings support the findings of the previous study that RB or 13q loss is specific for parathyroid tumors with increased aggressiveness and might be of clinical significance.

Correlated abnormalities of transforming growth factor-beta 1 response and p53 expression in thyroid epithelial cell transformation.

Using the thyroid follicular cell as a model for multi-stage carcinogenesis, we have investigated the role of two potential negative growth regulators ('anti-oncogenes') in epithelial tumour progression--transforming growth factor-beta 1 (TGF beta 1) and p53. Normal follicular cells, as expected, showed marked growth inhibition in response to TGF beta 1. Adenoma cells were equally inhibited. In contrast, spontaneously and SV40-immortalised follicular cell lines showing features of malignant transformation (notably loss of growth factor dependence) had lost all responsiveness to TGF beta 1, accompanied by a partial loss of its receptors. p53 protein was below detectable limits in normal and in adenoma cells but in contrast very high levels were observed in all three transformed lines. In the SV40-immortalised cells, this was expected in view of the known stabilising effect of the viral large T protein. In the spontaneous line we found strong evidence for point mutation of p53, which is known to have the same effect. Both mechanisms result in loss of p53 tumour suppressor function despite increased protein content. We conclude that loss of inhibition by TGF beta and inactivation of p53 are important steps in in vitro immortalisation and/or in vivo tumour progression in human thyroid follicular cells, and speculate that p53 may mediate or be required for the inhibitory signal normally induced by TGF beta 1.

Clinical management of malignant adrenal tumors.

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 improvement 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 doxorubicin or etoposide, appear to be effective in adrenocortical carcinoma. 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 phenoxybenzamine and metyrosine are available for malignant pheochromocytoma. This review provides guidelines for rational disease management based on still scanty clinical evidence.