The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). In total, 176 patients with single, multiple, and recurrent tumours were identified (1.84 tumours/patient, range 1–8). Mean age at diagnosis was 32 ± 16 years. Seventy-four percent of tumours were localised to the adrenals. Mean tumour diameter was 2.42 ± 2.27 cm, 46% were <1.5 cm. 24% of tumours were biochemically inactive. Inactive tumours were significantly smaller than active PHEO/PGL at diagnosis (4.16 ± 2.80 cm vs 1.43 ± 0.45 cm; P < 0.025) and before surgery (4.89 ± 3.47 cm vs 1.36 ± 0.43 cm; P < 0.02). Disease was stable in 67% of 21 patients with evaluable tumours ≤1.5 cm according to RECIST and progressed in 7. Time till surgery in these patients was 29.5 ± 20.0 months. A total of 155 patients underwent surgery. PHEO/PGL was histologically excluded in 4 and proven in 151. Of these, one had additional metastatic disease, one harboured another tumour of a different type, and in 2 a second surgery for suspected disease recurrence did not confirm PHEO/PGL. Logistic regression analysis revealed 50% probability for a positive/negative biochemical test result at 1.8 cm tumour diameter. Values of a novel symptom score were positively correlated with tumour size (Rs = 0.46, P < 0.0001) and together with a positive biochemistry a linear size predictor (P < 0.01). Results support standardised clinical assessment and measurement of tumour size and metanephrines in VHL patients with non-functioning incidentalomas <1.5 cm at one year following diagnosis and at individualised intervals thereafter depending on evolving growth dynamics, secretory activity and symptomatology.
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Roland Därr, Jonas Kater, Peggy Sekula, Birke Bausch, Tobias Krauss, Christoph Bode, Gerd Walz, Hartmut P Neumann, and Stefan Zschiedrich
Anastasia P Athanasoulia-Kaspar, Kathrin H Popp, and Gunter Karl Stalla
The dopaminergic treatment represents the primary treatment in prolactinomas, which are the most common pituitary adenomas and account for about 40% of all pituitary tumours with an annual incidence of six to ten cases per million population. The dopaminergic treatment includes ergot and non-ergot derivatives with high affinity for the dopamine receptors D1 or/and D2. Through the activation of the dopaminergic pathway on pituitary lactotrophs, the dopamine agonists inhibit the prolactin synthesis and secretion, therefore normalizing the prolactin levels and restoring eugonadism, but they also lead to tumour shrinkage. Treatment with dopamine agonists has been associated – apart from the common side effects such as gastrointestinal symptoms, dizziness and hypotension – with neuropsychiatric side effects such as impulse control disorders (e.g. pathological gambling, compulsive shopping, hypersexuality and binge eating) and also with behavioral changes from low mood, irritability and verbal aggressiveness up to psychotic and manic symptoms and paranoid delusions not only in patients with prolactinomas but also in patients with Parkinson’s disease and restless leg syndrome. They usually have de novo onset after initiation of the dopaminergic treatment and have been mainly reported in patients with Parkinson’s disease, who are being treated with higher doses of dopamine agonists. Moreover, dopamine and prolactin seem to play an essential role in the metabolic pathway. Patients with hyperprolactinemia tend to have increased body weight and an altered metabolic profile with hyperinsulinemia and increased prevalence of diabetes mellitus in comparison to healthy individuals and patients with non-functioning pituitary adenomas. Treatment with dopamine agonists in these patients in short-term studies seems to lead to weight loss and amelioration of the metabolic changes. Together these observations provide evidence that dopamine and prolactin have a crucial role both in the regard and metabolic system, findings that merit further investigation in long-term studies.
Serena Martinelli, Mario Maggi, and Elena Rapizzi
Pheochromocytomas/paragangliomas (PPGLs) are rare neuroendocrine tumours linked to more than 15 susceptibility genes. PPGLs present with very different genotype/phenotype correlations. Certainly, depending on the mutated gene, and the activated intracellular signalling pathways, as well as their metastatic potential, each tumour is immensely different. One of the major challenges in in vitro research, whatever the study field, is to choose the best cellular model for that study. Unfortunately, most of the time there is not ‘a best’ cell model. Thus, in order to avoid observations that could be related to and/or dependent on a specific cell line, researchers often perform the same experiments using different cell lines simultaneously. The situation is even more complicated when there are only very few cell models obtained in different species for a disease. This is the case for PPGLs. In this review, we will describe the characteristics of the different cell lines and of mouse models, trying to understand if there is one that is more appropriate to use, depending on which aspect of the tumours one is trying to investigate.
Magaly Zappa, Olivia Hentic, Marie-Pierre Vullierme, Matthieu Lagadec, Maxime Ronot, Philippe Ruszniewski, and Valérie Vilgrain
Visual semi-quantitative assessment of liver tumour burden for neuroendocrine tumour liver metastases is often used in patient management and outcome. However, published data on the reproducibility of these evaluations are lacking.
The aim of this study was to evaluate the interobserver and intraobserver agreement of a visual semi-quantitative assessment of liver tumour burden using CT scan.
Fifty consecutive patients (24 men and 26 women, mean aged 54 years) were retrospectively reviewed by four readers (two senior radiologists, one junior radiologist and one gastroenterologist) who assessed the liver tumour burden based on a visual semi-quantitative method with four classes (0–10, 11–25, 26–50 and ≥50%). Interobserver and intraobserver agreement were assessed by weighted kappa coefficient and percentage of agreement. The intraclass correlation was calculated.
Agreement among the four observers for the evaluation of liver tumour burden was substantial, ranging from 0.62 to 0.73 (P < 0.0001). The intraclass coefficient was 0.977 (P < 0.0001). Intraobserver agreement was 0.78 and ICC was 0.97.
Reproducibility of the visual semi-quantitative evaluation of liver tumour burden is good and is independent of the level of experience of the readers. We therefore suggest that clinical studies in patients with neuroendocrine liver metastases use this method to categorise liver tumour burden.
Nilesh Lomte, Tushar Bandgar, Shruti Khare, Swati Jadhav, Anurag Lila, Manjunath Goroshi, Rajeev Kasaliwal, Kranti Khadilkar, and Nalini S Shah
Bilateral adrenal masses may have aetiologies like hyperplasia and infiltrative lesions, besides tumours. Hyperplastic and infiltrative lesions may have coexisting hypocortisolism. Bilateral tumours are likely to have hereditary/syndromic associations. The data on clinical profile of bilateral adrenal masses are limited.
To analyse clinical, biochemical and radiological features, and management outcomes in patients with bilateral adrenal masses.
Retrospective analysis of 70 patients with bilateral adrenal masses presenting to a single tertiary care endocrine centre from western India (2002–2015).
The most common aetiology was pheochromocytoma (40%), followed by tuberculosis (27.1%), primary adrenal lymphoma (PAL) (10%), metastases (5.7%), non-functioning adenomas (4.3%), primary bilateral macronodular adrenal hyperplasia (4.3%), and others (8.6%). Age at presentation was less in patients with pheochromocytoma (33 years) and tuberculosis (41 years) compared with PAL (48 years) and metastases (61 years) (P<0.001). The presenting symptoms for pheochromocytoma were hyperadrenergic spells (54%) and abdominal pain (29%), whereas tuberculosis presented with adrenal insufficiency (AI) (95%). The presenting symptoms for PAL were AI (57%) and abdominal pain (43%), whereas all cases of metastasis had abdominal pain. Mean size of adrenal masses was the largest in lymphoma (5.5cm) followed by pheochromocytoma (4.8cm), metastasis (4cm) and tuberculosis (2.1cm) (P<0.001). Biochemically, most patients with pheochromocytoma (92.8%) had catecholamine excess. Hypocortisolism was common in tuberculosis (100%) and PAL (71.4%) and absent with metastases (P<0.001).
In evaluation of bilateral adrenal masses, age at presentation, presenting symptoms, lesion size, and biochemical features are helpful in delineating varied underlying aetiologies.
Felix Haglund, Gustaf Rosin, Inga-Lena Nilsson, C Christofer Juhlin, Ylva Pernow, Sophie Norenstedt, Andrii Dinets, Catharina Larsson, Johan Hartman, and Anders Höög
Primary hyperparathyroidism (PHPT) is a common endocrinopathy, frequently caused by a parathyroid adenoma, rarely by a parathyroid carcinoma that lacks effective oncological treatment. As the majority of cases are present in postmenopausal women, oestrogen signalling has been implicated in the tumourigenesis. Oestrogen receptor beta 1 (ERB1) and ERB2 have been recently identified in parathyroid adenomas, the former inducing genes coupled to tumour apoptosis. We applied immunohistochemistry and slide digitalisation to quantify nuclear ERB1 and ERB2 in 172 parathyroid adenomas, atypical adenomas and carcinomas, and ten normal parathyroid glands. All the normal parathyroid glands expressed ERB1 and ERB2. The majority of tumours expressed ERB1 (70.6%) at varying intensities, and ERB2 (96.5%) at strong intensities. Parathyroid carcinomas expressed ERB1 in three out of six cases and ERB2 in five out of six cases. The intensity of tumour nuclear ERB1 staining significantly correlated inversely with tumour weight (P=0.011), and patients whose tumours were classified as ERB1-negative had significantly greater tumour weight as well as higher serum calcium (P=0.002) and parathyroid hormone levels (P=0.003). Additionally, tumour nuclear ERB1 was not expressed differentially with respect to sex or age of the patient. Levels of tumour nuclear ERB2 did not correlate with clinical characteristics. In conclusion, decreased ERB1 immunoreactivity is associated with increased tumour weight in parathyroid adenomas. Given the previously reported correlation with tumour-suppressive signalling, selective oestrogen receptor modulation (SERMs) may play a role in the treatment of parathyroid carcinomas. Future studies of SERMs and oestrogen treatment in PHPT should consider tumour weight as a potential factor in pharmacological responsiveness.
Kate E Lines, Mahsa Javid, Anita A C Reed, Gerard V Walls, Mark Stevenson, Michelle Simon, Kreepa G Kooblall, Sian E Piret, Paul T Christie, Paul J Newey, Ann-Marie Mallon, and Rajesh V Thakker
Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.
Kranti Khadilkar, Vijaya Sarathi, Rajeev Kasaliwal, Reshma Pandit, Manjunath Goroshi, Gaurav Malhotra, Abhay Dalvi, Ganesh Bakshi, Anil Bhansali, Rajesh Rajput, Vyankatesh Shivane, Anurag Lila, Tushar Bandgar, and Nalini S Shah
Background and aims
Malignant transformation of pheochromocytomas/paragangliomas (PCC/PGL) is a rare occurrence, and predictive factors for the same are not well understood. This study aims to identify the predictors of malignancy in patients with PCC/PGL.
Materials and methods
We performed a retrospective analysis of 142 patients with either PCC or PGL registered at our institute between 2000 and 2015. Records were evaluated for clinical parameters like age, gender, familial/syndromic presentation, symptomatic presentation, biochemistry, size, number and location of tumours and presence of metastases and mode of its diagnosis.
Twenty patients were found to have metastases; 13 had metastases at diagnosis and seven during follow-up. Metastases were detected by radiology (CT-neck to pelvis) in 11/20 patients (5/13 synchronous and 6/7 metachronous), 131I-metaiodobenzylguanidine in five (2/12 synchronous and 3/6 metachronous) patients and 18F-flurodeoxyglucose PET/CT in 15 (12/12 synchronous and 3/3 metachronous) patients. Malignant tumours were significantly larger than benign tumours (8.3 ± 4.1 cm, range: 3–22 cm vs 5.7 ± 2.3 cm, range: 2–14 cm, P = 0.0001) and less frequently metanephrine secreting. On linear regression analysis, tumour size and lack of metanephrine secretion were the independent predictors of malignancy.
Patients with primary tumour size >5.7 cm and lack of metanephrine secretory status should be evaluated for possible malignancy not only at diagnosis but also in the postoperative period. As compared to CT and 131I-MIBG scan, 18F-flurodeoxyglucose PET/CT analyses are better (sensitivity: 100%) for the diagnosis of metastases in our study.
K E Lines, R P Vas Nunes, M Frost, C J Yates, M Stevenson, and R V Thakker
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreatic islets and anterior pituitary. The MEN1 gene, encoding menin, is a tumour suppressor, but its precise role in initiating in vivo tumourigenesis remains to be elucidated. The availability of a temporally controlled conditional MEN1 mouse model would greatly facilitate the study of such early tumourigenic events, and overcome the limitations of other MEN1 knockout models, in which menin is lost from conception or tumour development occurs asynchronously. To generate a temporally controlled conditional mouse model, we crossbred mice with the MEN1 gene floxed by LoxP sites (Men1 L/L), and mice expressing tamoxifen-inducible Cre recombinase under the control of the rat insulin promoter (RIP2-CreER), to establish a pancreatic β-cell-specific NET model under temporal control (Men1 L/L/RIP2-CreER). Men1 L/L/RIP2-CreER mice aged ~3 months were given tamoxifen in the diet for 5 days, and pancreata harvested 2–2.5, 2.9–3.5 and 4.5–5.5 months later. Control mice did not express Cre and did not receive tamoxifen. Immunostaining of pancreata from tamoxifen-treated Men1 L/L/RIP2-CreER mice, compared to control mice, showed at all ages: loss of menin in all islets; increased islet area (>4.2-fold); increased proliferation of insulin immunostaining β-cells (>2.3-fold) and decreased proliferation of glucagon immunostaining α-cells (>1.7-fold). There were no gender and apoptotic or proliferation differences, and extra-pancreatic tumours were not detected. Thus, we have established a mouse model (Men1 L/L/RIP2-CreER) to study early events in the development of pancreatic β-cell NETs.
Raluca Maria Furnica, Muhammad Muddaththir Dusoruth, Alexandre Persu, Damien Gruson, Michel Mourad, and Dominique Maiter
Surgery of pheochromocytomas (PCs) still carries a high risk of haemodynamic complications during the perioperative period. We aimed to evaluate the influence of their secretory phenotype and preoperative alpha-blocker treatment on surgical outcome.
A retrospective monocentric study at a tertiary medical centre.
In this study, 80 consecutive patients operated by the same team for a PC between 1988 and 2018.
Diagnosis was based on typical symptoms and signs in 58 patients, genetic testing in 12 and work-up of an adrenal incidentaloma in 9. It was made during surgery in one patient. A genetic predisposition was found in one-third of index cases (21/62). The majority of the patients (73/79) had a secreting PC; more than 2/3 had an adrenergic phenotype and less than 1/3 a noradrenergic phenotype. The rate of perioperative haemodynamic complications was not influenced by the secretory phenotype, but persistent hypertension after surgery, recurrence and malignancy were more frequently observed in patients with a noradrenergic tumour. Preoperative alpha-blocker treatment was given for ≥ 14 days in 29 patients and, although being more symptomatic at diagnosis, these patients had less haemodynamic complications (3/29 vs 12/51 non-treated patients, P = 0.05).
The occurrence of haemodynamic complications during surgery was not significantly affected by the secretory phenotype in our study, but noradrenergic tumours show a worse post-surgical outcome. Our data also provide additional support in favour of a sufficient preoperative alpha-blockade in patients with pheochromocytoma.