The immune cell infiltrate in the tumour microenvironment of phaeochromocytomas and paragangliomas.

Emerging evidence suggests the composition of the tumour microenvironment (TME) correlates with clinical outcome and that each tumour type has a unique TME including a variable population of inflammatory cells. We performed immunohistochemistry on 65 phaeochromocytoma and paraganglioma (PPGL) tumour samples with 20 normal adrenal medulla samples for comparison. The immune cells assessed were macrophages, lymphocytes and neutrophils, and we compared the proportion of infiltration of these immune cells with clinical and histopathological factors. There was a higher proportion of immune cells in tumour tissue compared to non-neoplastic adrenal medulla tissue, with a predominance of macrophages. There was a higher proportion of M2:M1 macrophages and T-helper lymphocytes in aggressive tumours compared to indolent ones. For SDHB-associated tumours, there was a higher proportion of M2 macrophage infiltration, with higher M2:M1 in aggressive SDHB PPGLs compared to indolent tumours. These data demonstrate that immune cells do infiltrate the TME of PPGLs, confirming that PPGLs are immunologically active tumours. Differences in the TME of PPGLs were observed between aggressive and indolent tumours. These differences could potentially be exploited as an aid in predicting tumour behaviour.

Monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia.

The surveillance strategy for patients taking low dose cabergoline for hyperprolactinaemia is controversial. As more evidence has emerged that the risks of cardiac valvulopathy in this population of patients are low, fewer and fewer endocrinologists adhere strictly to the original medicines and healthcare products agency MHRA guidance of "at least" annual echocardiography. Strict adherence to this guidance would be costly in monetary terms (£5.76 million/year in the UK) and also in resource use (90,000 extra echocardiograms/year). This article reviews the proposed pathophysiological mechanism underlying the phenomenon of dopamine agonist valvulopathy, the characteristic echocardiographic changes seen, summarises the published literature on the incidence of valvulopathy with low dose cabergoline and examines the previous and current evidence-based screening guidelines.

A meta-analysis of the prevalence of cardiac valvulopathy in hyperprolactinemic patients treated with Cabergoline.

CONTEXT: Cabergoline is first line treatment for most patients with lactotrope pituitary tumors and hyperprolactinemia. Its use at high-dose in Parkinson's disease has largely been abandoned, because of its association with the development of a characteristic restrictive cardiac valvulopathy. Whether similar valvular changes occur in patients receiving lower doses for treatment of hyperprolactinemia is unclear, although stringent regulatory recommendations for echocardiographic screening exist. OBJECTIVE: To conduct a meta-analysis exploring any link between the use of cabergoline for the treatment of hyperprolactinemia and clinically-significant cardiac valvulopathy. DATA SOURCES: Full-text papers published up to and including January 2017 were found via PubMed and selected according to strict inclusion criteria. STUDY SELECTION: All case-control studies were included where patients had received ≥6 months cabergoline treatment for hyperprolactinemia. Single case reports, previous meta-analyses, review papers and papers pertaining solely to Parkinson's disease were excluded. 13/76 originally selected studies met inclusion criteria. DATA EXTRACTION: A list of desired data were compiled and extracted from papers by independent observers. Each also independently graded for paper quality (bias) and met to reach consensus. DATA SYNTHESIS: More tricuspid regurgitation was observed (OR 3.74; 95% CI 1.79-7.8 p<0.001) in the cabergoline treated patients compared to controls. In no patient was tricuspid valve dysfunction diagnosed as a result of clinical symptoms. There was no significant increase in any other valvulopathy. CONCLUSIONS: Treatment with low dose cabergoline in hyperprolactinemia appears to be associated with an increased prevalence of tricuspid regurgitation. The clinical significance of this is unclear and requires further investigation. 51.

Phaeochromocytoma and Paraganglioma Excision Involving the Great Vessels.

OBJECTIVE/BACKGROUND: Phaeochromocytomas and paragangliomas are vascular neuroendocrine tumours distributed between the neck and the pelvis and may be associated with catecholamine secretion. The aim of the study was to describe the complex surgical management required to excise these tumours when in close proximity to the great vessels (aorta and vena cava). METHODS: This was a retrospective case series. Patients included those undergoing surgical excision of a phaeochromocytoma or paraganglioma involving the great vessels. Data on clinical presentation; genetic mutations; tumour location; catecholamine/metanephrine secretion; surgical strategy; pre-, intra-, and post-operative course were collated. RESULTS: Five patients (age range 16-60 years) were identified; three had thoracic paragangliomas located under the arch of the aorta, one had an abdominal paraganglioma invading the aorta, and one had a massive phaeochromocytoma invading the inferior vena cava via the adrenal vein. Three patients had predisposing germline mutations. All patients had adrenergic blockade prior to surgery. A diverse range of complex surgical techniques were employed to excise tumours, including cardiopulmonary bypass, aortic resection, grafting and venotomy of the vena cava. Early post-operative complications were limited. CONCLUSIONS: Excision of phaeochromocytomas and paragangliomas involving the great vessels is high risk surgery optimally undertaken within a multidisciplinary setting in a tertiary referral centre. Comprehensive radiological and biochemical assessment, meticulous pre-operative preparation and close intra- and post-operative monitoring are essential. Radiological imaging may be unable to resolve the tumour extent and anatomy pre-operatively and direct visualisation of the tumour may be the only way to clarify the surgical strategy. Pre-operative knowledge of the genetic predisposition may influence surgical management.

Clinical outcomes following unilateral adrenalectomy in patients with primary aldosteronism.

BACKGROUND: In approximately half of cases of primary aldosteronism (PA), the cause is a surgically-resectable unilateral aldosterone-producing adrenal adenoma. However, long-term data on surgical outcomes are sparse. AIM: We report on clinical outcomes post-adrenalectomy in a cohort of patients with PA who underwent surgery. DESIGN: Retrospective review of patients treated for PA in a single UK tertiary centre. METHODS: Of 120 consecutive patients investigated for PA, 52 (30 male, median age 54, range 30-74) underwent unilateral complete adrenalectomy. Blood pressure, number of antihypertensive medications, and serum potassium were recorded before adrenalectomy, and after a median follow-up period of 50 months (range 7-115). Recumbent renin and aldosterone were measured, in the absence of interfering antihypertensive medication, ≥3months after surgery, to determine if PA had been biochemically cured. RESULTS: Overall, blood pressure improved from a median (range) 160/95 mmHg (120/80-250/150) pre-operatively to 130/80 mmHg (110/70-160/93), P < 0.0001. 24/52 patients (46.2%) had cured hypertension, with a normal blood pressure post-operatively on no medication. 26/52 (50%) had improved hypertension. 2/52 patients (3.8%) showed no improvement in blood pressure post-operatively. Median (range) serum potassium level increased from 3.2 (2.3-4.7) mmol/l pre-operatively to 4.4 mmol/l (3.3-5.3) post-operatively, P < 0.0001). Median (range) number of antihypertensive medications used fell from 3 (0-6) pre- to 1 post-operatively (range 0-4), P < 0.0001. CONCLUSIONS: Unilateral adrenalectomy provides excellent long-term improvements in blood pressure control, polypharmacy and hypokalaemia in patients with lateralizing PA. These data may help inform discussions with patients contemplating surgery.

Four generations of SDHB-related disease: complexities in management.

SDHB mutations are linked to the familial paraganglioma syndrome type 4 (PGL4), which is associated with predominantly extra-adrenal disease and has high metastatic rates. Despite the lower penetrance rates in carriers of SDHB mutations compared to mutations in other paraganglioma susceptibility genes, the aggressive behavior of SDHB-linked disease warrants intensive surveillance to identify and resect tumors early. Patients with similar SDHB genotypes in whom the PGL syndrome manifests often exhibit very heterogeneous phenotypes. Tumors can arise in various locations, and management can be considerably different, depending on tumor site and pathology. We present a case series of five SDHB mutation carriers over four generations from the same family to illustrate the complexities in management.

Circadian variation in serum cortisol during hydrocortisone replacement is not attributable to changes in cortisol-binding globulin concentrations.

BACKGROUND: Patients taking hydrocortisone (HC) replacement for primary or secondary adrenal failure require individual adjustment of their dose. In addition to modifying the administered doses of HC for each patient, physicians are increasingly interested in variations in the bioavailability of glucocorticoid replacement. One potential determinant of the bioavailability of replaced HC is a variation in serum cortisol-binding globulin (CBG) concentration, which may, in turn, affect interpretation of cortisol profiles and individual dose selection for patients on hydrocortisone replacement therapy. AIM: To investigate the hypothesis that there is a circadian variation in CBG levels. METHODS AND RESULTS: A total of 34 male patients divided into 3 groups (10 patients with non-somatotroph structural pituitary disease on HC replacement, 11 patients with treated acromegaly on HC replacement and 13 patients with treated acromegaly not on HC replacement) and 10 healthy volunteers were included. Cortisol and CBG levels were measured at 6 time points (0800, 1100, 1300, 1500, 1700 and 1900). No significant circadian variation in CBG concentration was found in any of the 4 groups. CONCLUSION: Circadian variation in serum cortisol during hydrocortisone replacement is not attributable to changes in cortisol-binding globulin concentration. Changes in serum cortisol levels may thus be explained by other factors including 11 ß-hydroxysteroid dehydrogenase type 1 activity or circadian changes in the binding properties of CBG.

Contemporary surgical treatment of primary hyperparathyroidism without intraoperative parathyroid hormone measurement.

INTRODUCTION: Primary hyperparathyroidism (pHPT) is usually the result of a single adenoma that can often be accurately located preoperatively and excised by a focused operation. Intraoperative parathyroid hormone (IOPTH) measurement is used occasionally to detect additional abnormal glands. However, it remains controversial as to whether IOPTH monitoring is necessary. This study presents the results of a large series of focused parathyroidectomy without IOPTH measurement. METHODS: Data from 2003 to 2014 were collected on 180 consecutive patients who underwent surgical treatment for pHPT by a single surgeon. Preoperative ultrasonography and sestamibi imaging was performed routinely, with computed tomography (CT) and/or selective venous sampling in selected cases. The preferred procedure for single gland disease was a focused lateral approach guided by on-table surgeon performed ultrasonography. Frozen section was used selectively and surgical cure was defined as normocalcaemia at the six-month follow-up appointment. RESULTS: Focused surgery was undertaken in 146 patients (81%) and 97% of these cases had concordant results with two imaging modalities. In all cases, an abnormal gland was discovered at the predetermined site. Of the 146 patients, 132 underwent a focused lateral approach (11 of which were converted to a collar incision), 10 required a collar incision and 4 underwent a mini-sternotomy. At 6 months following surgery, 142 patients were normocalcaemic (97% primary cure rate). Three of the four treatment failures had subsequent surgery and are now biochemically cured. There were no complications or cases of persistent hypocalcaemia. CONCLUSIONS: This study provides further evidence that in the presence of concordant preoperative imaging, IOPTH measurement can be safely omitted when performing focused parathyroidectomy for most cases of pHPT.