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.

[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.

[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.

Failed surgery in primary hyperparathyroidism - what has changed with time.

Advanced preoperative imaging of parathyroid adenomas and intraoperative parathyroid hormone determination optimized the results in the surgical treatment of primary hyperparathyroidism patients. We asked, whether reasons for failure have changed during the last 25 years.We retrospectively analyzed operations for persistent primary hyperparathyroidism in our department between 2001 and 2011 (n=67), and compared these results to our experience between 1986 and 2001 (n=80).From 2001 to 2011, 765 primary hyperparathyroidism patients were operated on at our department. All but 4 patients were cured (761/765, 99.5%). 67 operations were performed for persistent primary hyperparathyroidism. Main reasons for failure were a misdiagnosed sporadic multiple gland disease in our own patients (18/29, 62.1%), and an undetected solitary adenoma in patients referred to us after -initial operation in another hospital (22/38, 57.9%) (statistically significant). From 1986 to 2001 (1 105 primary hyperparathyroidism patients), main indications for re-operation due to persistent disease were an undiagnosed sporadic multiple gland disease in our own patients (15/24, 62.5%), and a missed solitary adenoma in patients being operated on primarily somewhere else (38/56, 67.9%) (statistically significant).Comparing our experience in 147 patients with persistent primary hyperparathyroidism being operated on between 2001-2011 and 1986-2001, not much has changed with the modern armamentarium of improved preoperative imaging or intraoperative biochemical control. Whereas sporadic multiple gland disease was the most common reason for unsuccessful surgery in experienced hands, other units mainly failed due to an undetected solitary adenoma. Re-operations for persistent primary hyperparathyroidism performed by us were successful in 93.8% (2001-2011) and 96.0% (1986-2001), respectively.

[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.

[Diagnostics and treatment in functional pancreatic neuroendocrine tumours]. / Diagnostik und Therapie bei funktionell aktiven pankreatischen neuroendokrinen Tumoren.

Pancreatic neuroendocrine tumours (PNET) are rare entities with an annual incidence of < 100,000. About 1 - 2 % of pancreatic neoplasias are neuroendocrine tumours. About one third of these tumours secrete biologically active substances that lead to development of specific clinical syndromes. PNET may occur sporadically or in association with hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN1). Among the functional PNET, insulinomas and gastrinomas are the most common entities. In contrast, vasoactive intetinale peptide (VIP)-secreting tumours, glucagonomas, serotonin-secreting carcinoid tumors, and tumours with secretion of ectopic hormones, such as calcitonin, are extremely rare. Once diagnosis has been established on the basis of clinical and laboratory findings, localization of the source of pathologic hormone secretion is warranted. Imaging methods frequently used for localization of PNET comprise anatomical imaging modalities, computed tomography, and magnetic resonance imaging, endoscopic ultrasound, selective arterial catheterization with hepatic venous sampling, DTPA-octreotid scintigraphy and DOTA-D-Phe(1)-Tyr(3)-octreotid positron emission tomography. Therapy is based on the specific tumour entity and the extent of the disease. In the majority of patients, even in the case of malignant disease, a surgical approach is warranted, eventually combined with a medical treatment.

Extra-adrenal pheochromocytoma in the organ of Zuckerkandl: diagnosis and treatment strategies.

Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare catecholamine-secreting neuroendocrine tumors arising from chromaffin tissue and can occur within the adrenal medulla (PHEO) or extra-adrenal sites (PGL). The most common site for PGL is the organ of Zuckerkandl, extra-adrenal chromaffin tissue near the origin of the inferior mesenteric artery.We here present 2 patients with extra-adrenal PGL in the organ of Zuckerkandl, located by iodine-123-metaiodobenzylguanadine ( (123)I-MIBG) scintigraphy and thereafter treated surgically or with iodine-131-metaiodobenzylguanadine ( (131)I-MIBG). First, in a 15-year-old boy with clinical suspicion of PHEO, the diagnosis was established by biochemical evaluation and confirmed by further imaging studies, including CT and (123)I-MIBG, as PGL in the Zuckerkandl organ. The tumor was completely resected by laparotomy. Second, in a 70-year-old woman presenting with progressive hypertension and palpitations, MR and (123)I-MIBG revealed a singular tumor lesion with abnormal (123)I-MIBG uptake in the Zuckerkandl organ. Due to severe general vascular disease, surgery was not performed and instead the patient underwent (131)I-MIBG therapy. The patient showed a good symptomatic response with improvement of symptoms and no relevant side-effects of therapy.

[Insulinoma associated with pregnancy]. / Postpartales Insulinom.

HISTORY AND CLINICAL FINDINGS: A 42-year-old woman was found by her husband with unconsciousness and seizure at night three weeks after delivery of her fifth child. At a blood glucose level of 25 mg/dl, she received an intravenous infusion of glucose by the called emergency physician, leading to a rapid improvement of her symptoms. INVESTIGATION AND DIAGNOSIS: The following examination showed a low basal blood glucose level as well as pathological levels of insulin and C-peptide. These findings together with the Whipple trias (hypoglycaemia, neurological symptoms and rapid improvement after infusion of glucose) were highly suspicious of an insulinoma. Whereas CT, MRI and DOTATOC-PET were negative, endoscopic ultrasound showed a mass of 13 mm in the tail of the pancreas. TREATMENT AND COURSE: The tumour was resected from the tail of the pancreas by laparoscopic enucleation. Histological examination revealed an endocrine tumour (insulinoma) of the pancreas. Postoperative blood glucose levels were within the normal range. The patient and her healthy newborn child could be dismissed from hospital on the third day after surgery. CONCLUSION: Despite its rarity, an insulinoma represents an important differential diagnosis of hypoglycaemia during and right after pregnancy.

[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.

[Indication and performance of endocrine surgery. The significance of molecular genetic examination]. / Indikation und Durchführung endokrin-chirurgischer Operationen. Bedeutung molekulargenetischer Untersuchungen.

The molecular genetic changes from certain endocrine tumors are already understood, reflecting as they do the etiology of these sporadic familial disorders. This already has clinical consequences to the treatment of familial endocrine tumors, which often appear in the course of syndromatic disorders. These consequences consist in slight changes to surgical technique, the search for other active and usually endocrinal tumors, and examination of family members for other gene carriers (of disease-specific mutations) and the most suitable prophylactic tumor therapy. In contrast, for sporadic endocrine tumors there exists far less clinically relevant knowledge. Starting with anamnesis and clinical findings of active endocrine tumors, we discuss the current possibilities for molecular genetic determination of disease-specific mutations (germline and tumor DNA) and their effect on surgical procedure.

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.

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.