[Pheochromocytomatosis after adrenalectomy: metastasis or cell seeding?] / Phäochromozytomatose nach Adrenalektomie: Metastasierung oder Zellverschleppung?

Pheochromocytomatosis is defined as a multifocal cell dissemination limited to the operatively opened space with no signs of distant metastasis. After primary adrenalectomy due to a pheochromocytoma this is a rare and underrecognized manifestation of a tumor recurrence. Between 2010 and 2019 a total of 5 patients with the presentation of pheochromocytomatosis were treated in this center. Clinical and survival data were compared to 12 patients with a metastasized pheochromocytoma. Patients presenting with pheochromocytomatosis showed a better but not significant overall survival (136.8 vs. 107 months). Furthermore, patients with pheochromocytomatosis presented more often with a noradrenaline secretion type. Tumor recurrence in the pheochromocytomatosis group occurred on average 69.2 months after the initial diagnosis and was therefore much later than in patients with distant metastases from a pheochromocytoma (39 months, p = 0.13). This article outlines this special manifestation of recurrence of a pheochromocytoma based on this patient collective. Besides technical operative aspects there appears to be evidence for tumor-specific factors that promote the development of pheochromocytomatosis. Importantly, it seems that all patients with a pheochromocytoma should receive lifelong aftercare and that patients should be closely monitored during the first 5 years after surgery.

[Somatostatin receptor PET/CT (SSTR-PET/CT)]. / Somatostatinrezeptor-PET/CT.

The present guideline is focused on quality assurance of somatostatin receptor PET/CT (SSTR-PET/CT) in oncology patients. The document has been developed by a multidisciplinary board of specialists providing consensus of definitions, prerequisites, methodology, operating procedures, assessment, and standardized reporting. In particular, imaging procedures for the two most commonly used radioligands of human SSTR, i. e. 68Ga-DOTATOC and 68Ga-DOTATATE are presented. Overall, SSTR-PET/CT requires close interdisciplinary communication and cooperation of referring and executing medical disciplines, taking into account existing guidelines and recommendations of the European and German medical societies, including the European Association of Nuclear Medicine (EANM), German Society for Endocrinology (DGE), German Society for Nuclear Medicine (DGN) and German Society for Radiology (DRG).

Sunitinib Efficacy in Patients with Advanced pNET in Clinical Practice.

Sunitinib treatment leads to improvement in progression-free survival in patients with advanced pancreatic neuroendocrine tumours (pNETs). However, limited data exist regarding the effectiveness, safety and tolerability in clinical practice. We present the results of the first detailed pNET cohort analysis since sunitinib was approved. Patients with advanced, differentiated pNET treated with sunitinib were retrospectively analysed. All patients had progressive disease before start of sunitinib treatment. Twenty-one patients, with a median age of 64 years (range 28-78), were included in this study. Nineteen patients could be analysed for treatment effectiveness. Twelve (57%) patients exhibited either a partial response (1 patient) or stable disease (11 patients) according to the RECIST criteria. The median progression-free survival was 7.0 months (95% CI 3.0-12.0); the probability of being event-free at 6 months was 52.6% (95% CI 28.4-72.1). Potential influencing factors as Ki-67 index, age or duration of disease did not show significant correlations with the response to sunitinib therapy. Considering the differences in patients' characteristics, sunitinib in daily practice showed effectiveness parameters similar to the phase III trial.

[Pancreatic neuroendocrine neoplasms]. / Neuroendokrine Neoplasien des Pankreas.

Pancreatic neuroendocrine neoplasms (NEN) account for 1-2% of all pancreatic neoplasms and represent a rare differential diagnosis. While some pancreatic NEN are hormonally active and exhibit endocrine activity associated with characteristic symptoms, the majority are hormonally inactive. Imaging techniques such as ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) or as combined PET/CT play a crucial role in the initial diagnosis, therapy planning and control. Endoscopic ultrasound (EUS) and multiphase CT represent the reference methods for localization of the primary pancreatic tumor. Particularly in the evaluation of small liver lesions MRI is the method of choice. Somatostatin receptor scintigraphy and somatostatin receptor PET/CT are of particular value for whole body staging and special aspects of further therapy planning.

[Neuroendocrine neoplasms of the breast]. / Neuroendokrine Neoplasien der Mamma.

Neuroendocrine neoplasms (NEN) of the breast are specific tumor entities. According to the literature up to 5% of breast neoplasms are malignant epithelial neoplasms of the breast. They are defined by a neuroendocrine (NE) architecture and cytology combined with an expression of the neuroendocrine vesicle markers chromogranin A and/or synaptophysin. The diagnosis is supplemented by the receptor status and the proliferative activity. According to the World Health Organization (WHO) classification of 2012 the following groups of NEN are distinguished: (1) invasive breast carcinoma with NE differentiation, (2) well-differentiated neuroendocrine tumor (NET) and (3) poorly differentiated small cell carcinoma (NEC). This review article focuses on (1) the definition and basic principles of diagnostics, (2) the history, nomenclature and WHO classification from 2003 and 2012, (3) the frequency of breast NEN, (4) the hereditary background and functional activity, (5) the expression of receptors and (6) the possible clinical implications. In addition, the first results of a retrospective single center study (n = 465 patients with breast cancer over a time period of 4 years) on the frequency of NEN of the breast at the Breast Center of the University Hospital Düsseldorf are presented. In this study a frequency of 4.5% of NEN was found based on a diagnostic cut-off of > 50% Chromogranin A and/or synaptophysin positive tumor cells.

[Peptide receptor radionuclide therapy for patients with somatostatin receptor expressing tumours. German Guideline (S1)]. / Peptidrezeptor-Radionuklidtherapie Somatostatinrezeptor-exprimierender Tumore. DGN-Leitlinie (S1).

This document describes the guideline for peptide receptor radionuclide therapy (PRRT) published by the German Society of Nuclear Medicine (DGN) and accepted by the Association of the Scientific Medical Societies in Germany (AWMF) to be included in the official AWMF Guideline Registry. These recommendations are a prerequisite for the quality management in the treatment of patients with somatostatin receptor expressing tumours using PRRT. They are aimed at guiding nuclear medicine specialists in selecting likely candidates to receive PRRT and to deliver the treatment in a safe and effective manner. The recommendations are based on an interdisciplinary consensus. The document contains background information and definitions and covers the rationale, indications and contraindications for PRRT. Essential topics are the requirements for institutions performing the therapy, e. g. presence of an expert for medical physics, intense cooperation with all colleagues involved in the treatment of a patient, and a certificate of instruction in radiochemical labelling and quality control are required. Furthermore, it is specified which patient data have to be available prior to performance of therapy and how treatment has to be carried out technically. Here, quality control and documentation of labelling are of great importance. After treatment, clinical quality control is mandatory (work-up of therapy data and follow-up of patients). Essential elements of follow-up are specified in detail. The complete treatment inclusive after-care has to be realised in close cooperation with the involved medical disciplines. Generally, the decision for PRRT should be undertaken within the framework of a multi-disciplinary tumour board.

[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.

[Influence of the calcitonin assay on the definition of biochemical cure in patients with medullary thyroid carcinoma]. / Assay-Abhängigkeit der Calcitonin-Zielbereiche für "biochemisch geheilte" Patienten mit medullärem Schilddrüsenkarzinom.

AIM: Calcitonin (hCT) is an important diagnostic parameter in medullary thyroid carcinoma (MTC). We determined the variability of the reference ranges of several currently available immunometric assays for "biochemically cured" MTC patients. PATIENTS, METHODS: We compared six assays [Nichols ICMA, Biomerica IEMA, Immulite 2000 (Siemens), Calcitonin-IRMA magnum (Medipan), SELco-IRMA (Medipan) and Calcitonin IRMA (Medgenix)] in subgroups of 198 patients with differentiated thyroid cancer (DTC) after total thyroidectomy as a model for curatively treated MTC patients. In addition, hCT was measured after pentagastrin stimulation in 13 DTC patients and 13 patients with MTC. RESULTS: The basal hCT concentrations were below the detection limit of the respective assay in 100% of all thyroidectomized DTC patients for Nichols ICMA (n = 138) and Immulite 2000 (n = 60), in 97% for Biomerica IEMA (n = 57), and in 85% for IRMA magnum (n = 20). However, basal hCT was mostly within the reference range in Selco-IRMA (n = 20) and Medgenix IRMA (n = 76). In all DTC patients and 9/13 MTC patients the pentagastrin stimulated hCT was below the detection limit for the Nichols ICMA and Immulite 2000, all four MTC patients with elevated stimulated hCT developed a recurrence during follow-up. CONCLUSIONS: For assays with high monomer specificity (Nichols ICMA, Biomerica IEMA, Immulite 2000, to a lesser degree IRMA magnum) biochemical cure is defined by basal and stimulated calcitonin levels below the detection limit. For assays with low monomer specificity (SELco-IRMA, IRMA Medgenix) calcitonin levels in the reference range of patients without thyroid diseases are consistent with "biochemical cure".

Chemotherapy in patients with progressive, undifferentiated neuroendocrine tumors: a single-center experience.

Treatment of patients with undifferentiated and histologically confirmed neuroendocrine tumors (NET) usually includes chemotherapeutic intervention. This retrospective study evaluated the outcome of 2 such chemotherapies. 18 patients (11 males; age 56.2 ± 2.5) with proven progressive disease were enrolled (mean Ki-67 34 ± 5%). Patients were treated from 2005 to 2007 with regimen A (carboplatin, etoposide, paclitaxel), and from 2007 to 2009 with regimen B (cisplatin, etoposide). This change was due to low tolerability of regimen A. The standard imaging procedure was computed tomography. 8 patients underwent treatment with regimen A (mean 3.3 ± 0.7 courses). Due to severe side effects, 3 patients had their therapy prematurely discontinued. The treatment responses of 6 patients who received more than 1 course were: 0% complete response (CR), 17% partial response (PR), 50% stable disease (SD), and 33% progressive disease (PD). The median progression free survival (PFS) was 6.7 months (range 3.2-10.0). In contrast, 12 patients received regimen B (mean 3.8 ± 0.4 courses), and none of them dropped out because of side effects. The overall responses were: 0% CR, 17% PR, 42% SD, and 42% PD. The median PFS was 6.3 months (range 2.8-26.4). The response rates of both regimes were not statistically different. Patients who were treated with regimen B demonstrated comparable PFS and less severe side effects than patients who received regimen A. However, patients need to be aware of the relatively short PFS time. In order to improve therapeutic outcome of patients with progressive undifferentiated NET, new therapeutic approaches and larger multi-center studies are needed.

Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine: a single-center experience.

OBJECTIVE: Experience with chemotherapy in patients with medullary thyroid carcinomas (MTC) is limited. This retrospective study evaluated the outcome of a combination of cyclophosphamide, vincristine, and dacarbazine ('CVD-regimen'), which has previously been suggested for treatment of malignant pheochromocytomas. METHODS: 9 patients (5 males; age 55.0 ± 4.0 years) with MTC were enrolled. Prior to chemotherapy, progressive disease was established in all patients by use of WHO criteria. On day 1 of each cycle, patients started with cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2), and dacarbazine 600 mg/m(2); on day 2, patients received dacarbazine alone (600 mg/m(2)). Treatment cycles were repeated at 21-day intervals and 6 cycles were planned for each patient. The standard imaging procedure was computed tomography, and the primary end point was the objective tumor response rate. After chemotherapy, patients were followed up until progression. RESULTS: 9 patients underwent a total of 57 cycles (mean 6.3 ± 0.3 cycles). Treatment responses were: 0% complete response, 11% partial response, 56% stable disease, and 33% progressive disease. The median progression free survival was 13.6 months (range 5.8-24.2 months). The median change (baseline vs. end of treatment) of calcitonin was -19% (range -70% to +174%). Reversible myelosuppression and moderate gastrointestinal symptoms were the most common adverse events. CONCLUSION: Although objective tumor response rates were low, the CVD regimen allowed disease stabilization for a substantial period of time and had acceptable toxicity. After initial surgery, chemotherapy may therefore be considered as a medical treatment option.

Recovery of pituitary function in the late-postoperative phase after pituitary surgery: results of dynamic testing in patients with pituitary disease by insulin tolerance test 3 and 12 months after surgery.

UNLABELLED: The insulin tolerance test (ITT) is considered the gold standard for assessment of GH and ACTH reserve in patients with pituitary disease following pituitary surgery and is usually performed after 6-12 weeks. However, abnormal axes may not be completely recovered by then. The aim of this study was to evaluate dynamic testing 3 and 12 months after transsphenoidal pituitary surgery. DESIGN AND PATIENTS: Serial dynamic testing was performed in 36 patients (13 women, age 18-78) at 3 and 12 months after transsphenoidal surgery. RESULTS: Compared with 3-month results, median GH peak levels during ITT after 12 months increased by 38% (P<0.05). In patients initially classified as GH deficiency (GHD), median GH peak increased after 12 months by 23% (P<0.05). At 3 and 12 months, 36% (13/36) and 47% (17/36) were GH sufficient respectively. Median cortisol peak levels after 12 months increased by 17% (P<0.01) compared with 3-month ITT. In ACTH-insufficient (AI) patients, peak cortisol levels increased significantly by 12% (P<0.05) at 12 months, and in ACTH-sufficient patients, peak cortisol levels increased significantly by 13% (P<0.05). At 12 months, there was recovery from AI in 11% of the patients, and recovery from GHD in 11% of patients. CONCLUSIONS: Serial dynamic testing results in a change in classification by ITT results in a relevant proportion of patients. Dynamic testing should be repeated during follow-up.

[Diagnosis and treatment of autoimmune thyroiditis]. / Diagnostik und Therapie der Immunthyreoiditis. Substituieren Sie, bevor die Hypothyreose manifest wird!

In Germany, autoimmune thyroiditis usually manifests as atrophic thyroiditis with functional hypothyroidism affecting elderly women in particular. Sonography and thyroid peroxidase antibodies (TPO antibodies) point the way to the diagnosis. Manifest hypothyroidism always requires substitution with levothyroxine. Many patients with subclinical hypothyroidism, especially those with positive thyroid antibodies, benefit from at least partial thyroxine substitution. Early treatment not only alleviates the clinical symptoms, but may possibly also diminish the associated cardiovascular risk. In pregnant and sterile women subclinical hypothyroidism should always be treated.

Diagnosis of adrenal insufficiency: Evaluation of the corticotropin-releasing hormone test and Basal serum cortisol in comparison to the insulin tolerance test in patients with hypothalamic-pituitary-adrenal disease.

The aim of the study was to evaluate the diagnostic value of the human CRH test and the basal morning serum cortisol for the diagnosis of adrenal insufficiency. Putative peak cortisol cut points for the CRH test and basal cortisol cut points were determined by receiver operating characteristic (ROC) analysis with the insulin tolerance test as reference test. Fifty-four patients with suspected hypothalamic-pituitary-adrenal disease were tested. In 20 healthy controls, CRH led to a mean peak cortisol of 594.8 +/- 21.7 nmol/liter. The lower limit of a normal response was calculated as 400 nmol/liter. ROC analysis of peak cortisol levels during CRH testing of patients with suspected hypothalamic-pituitary-adrenal disease suggested an optimal peak cortisol cut point of < or 377 nmol/liter for the diagnosis of adrenal insufficiency and a 96% specificity but poor sensitivity of 76%. The baseline cortisol in the healthy control group showed a mean of 439.3 +/- 24.9 nmol/liter, resulting in a lower limit of 267 nmol/liter. ROC analysis of patients suggested the highest accuracy for basal cortisol levels of 285 nmol/liter or more for the diagnosis of adrenal insufficiency (100% sensitivity and 61% specificity). Within this patient group, a cortisol of more than 98 nmol/liter excluded adrenal insufficiency among those without the disorder, yielding 100% specificity. Using these criteria of upper (285 nmol/liter) and lower (98 nmol/liter) cut-off points with high sensitivity and specificity can reduce the number of individuals who need provocative tests. Basal cortisol is less expensive, and we therefore suggest to use it as a first-line test of adrenal insufficiency. Because of the low sensitivity of the human CRH test, we do not recommend it as a second test.

[Rhabdomyolysis, hyponatremia and fever in a patient with Schmidt's syndrome]. / Rhabdomyolyse, Hyponatriämie und Fieber bei einem Patienten mit Schmidt-Syndrom.

HISTORY: A 38-year-old man had fever (40 degrees C) and a swollen right leg. Two weeks before admission he had received non-steroid anti-inflammatory drugs (paracetamol and ibuprofen) after a tooth extraction. Some weeks before he had noticed a rough voice and a dry skin. INVESTIGATIONS: The patient had a sinus tachycardia of 145/min (blood pressure of 130/80 mm Hg). Laboratory data revealed a CK of 16,650 U/l (< 80 U/l), myoglobin of 2420 U/l (< 90 microg/l) and LDH of 1250 U/l (<240 U/l), leukocyte count of 12,000 / microl and C-reactive protein of 3.0 mg/dl (<0.5 mg/dl). Sodium was markedly decreased (110 mmol/l (135 - 145 mmol/l)). Determination of thyroid hormone showed primary hypothyroidism with an elevated TSH of 62.6 mU/l (0.3 - 4.0 mU/l); T4 of 38 nmol/l (58 - 154 nmol/l), T3 1.17 of nmol/l (1.23 - 3.08 nmol/l) and fT4 of 6 pmol/l (10 - 25 pmol/l). The thyroid autoantibodies were increased (thyroxine peroxidase antibodies of 684 U/l (<35 U/l) and thyroglobulin antibodies of 173 U/l (<40 U/l)). Ultrasound of the thyroid revealed an nonhomogeneous structure. Cortisol at 8.00 a. m. was reduced by 63 mmol/l (180 - 640 mmol/l) and did not increase after administration of ACTH (60 min. cortisol at 90 mmol/l (>550 mmol/l)). ACTH was increased (141 pg/ml; normal range 17 - 52 pg/ml). TREATMENT AND COURSE: The initial therapy consisted of hydrocortisone (100 mg i.v as bolus and 100 mg during the next 24 hours) and levothyroxine replacement (200 micro g) was initiated. During the following 8 days clinical symptoms regressed. Values of sodium, myoglobin and LDH decreased. After therapy with cephalosporin (Ceftriaxon) and penicillin (Flucloxacillin) fever and inflammation parameters decreased. CONCLUSION: This is a rare case of a rhabdomyolysis and hyponatriaemia due to hypothyroidism and Addison's disease (Schmidt's syndrome).

Effects of growth hormone replacement therapy on levels of cortisol and cortisol-binding globulin in hypopituitary adults.

OBJECTIVE: To determine if human growth hormone (hGH) replacement therapy alters pharmacokinetics of hydrocortisone (CS) substitution in hypopituitary adults. DESIGN: To this aim, we analysed serum and salivary CS profiles 270 min after oral CS administration at baseline and 6 and 12 months after initiation of hGH replacement therapy. METHODS: Serum IGF-I, cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG) and sex hormone-binding hormone (SHBG) were measured using commercially available radioimmunoassays. In-house immunofluorometric assays were employed for measurements of CS and hGH. RESULTS: hGH replacement did not change total serum CS bioavailability (area under the serum cortisol profile curve). Interference of orally administered CS with salivary measurement of free CS (fCS) caused significant bias. Therefore, fCS levels were calculated from their total CS and cortisol-binding globulin (CBG) levels. CBG decreased by approximately 30% after both 6 and 12 months of hGH replacement therapy (n=20, P<0.01). A significant negative correlation between deltaCBG (CBG6months-CBGbaseline) and deltaIGF-I (IGF-I6months-IGF-Ibaseline) was observed (P=0.04). The calculated values of free CS tended to increase with physiological hGH replacement, but this effect was marginal and did not reach statistical significance. In contrast to the CBG concentrations, plasma levels of sex hormone-binding globulin and thyroxine-binding globulin were essentially stable. CONCLUSION: Given that no clinically relevant alterations in pharmacokinetics of CS were evoked by initiation of hGH replacement in hypopituitary adults, we conclude that CS substitution does not require dose adjustment after initiation of hGH replacement.