Maternal pheochromocytoma and childbirth in Sweden 1973-2015: a population-based study on short and long-term outcome.

PURPOSE: Data guiding management of pheochromocytoma and paraganglioma (PPGL) in pregnant women is limited, and long-term effects on the child are unknown. The aim of this retrospective registry-based case-cohort study was to assess how maternal PPGL and treatment impacts maternal and fetal outcome, including long-term outcome for the child. The main outcomes were maternal and fetal mortality and morbidity at delivery and relative healthcare consumption in children born by mothers with PPGL during pregnancy. METHODS: The National Birth Register identified 4,390,869 pregnancies between 1973-2015. Data was crosslinked with three Swedish national registers to identify women diagnosed with pheochromocytoma or paraganglioma within one year before or after childbirth. Hospital records were reviewed and register data was collected for five age-matched controls for each child until age 18. RESULTS: 21 women and 23 children were identified (incidence 4.8/1.000.000 births/year), all women with adrenal pheochromocytomas (Pc). The majority (71%) were diagnosed post-partum. Nine women (43%) were hypertensive during pregnancy. Preterm delivery was more common in Pc patients compared to controls (30% vs 6%, p < 0.001). There was no maternal or fetal mortality. Timing of tumor removal did not affect gestational weight or APGAR scores. There was no observed difference in hospital admissions between children affected by maternal Pc and controls. CONCLUSION: Pc was commonly diagnosed after delivery and raised the risk of pre-term delivery, suggesting a need for an increased awareness of this diagnosis. However, reassuringly, there was no fetal or maternal mortality or any observed long-term impact on the children.

Mortality in Patients With Primary Aldosteronism: A Swedish Nationwide Study.

BACKGROUND: Primary aldosteronism (PA) is associated with increased mortality. The extent to which this phenomenon is affected by sex, age, comorbidities at diagnosis, and different treatment modalities is largely unknown. The objective was to determine all-cause and cause-specific mortality in a population-based cohort of patients with PA and the impact of age at diagnosis, sex, comorbidities, and treatment modalities. METHODS: We used national registers to identify patients diagnosed with PA between 1997 and 2019 (n=2419) and controls (n=24 187) from the general population, matched for sex, age, and county of residence. We obtained mortality data from the Cause-of-Death Register. We used Cox regression models, adjusted for socioeconomic factors and diabetes, to estimate adjusted hazard ratios (HRs [95% CI]). RESULTS: Overall, 346 (14.3%) patients with PA and 2736 (11.3%) controls died during a median follow-up time of 8.1 years. PA was associated with increased risk from all-cause mortality (HR, 1.23 [95% CI, 1.10-1.38]), death from cardiovascular disease (HR, 1.57 [95% CI, 1.30-1.89]), and stroke (HR, 1.85 [95% CI, 1.16-2.93]). Patients with cardiovascular disease at diagnosis (HR, 1.53 [1.26-1.85]), age >56 years (HR, 1.28 [95% CI, 1.13-1.45]), patients treated with a low dose of a mineralocorticoid receptor antagonist (HR, 1.30 [95% CI, 1.02-1.66]), and untreated patients (HR, 2.51 [95% CI, 1.72-3.67]) had excess mortality. CONCLUSIONS: Mortality, mainly due to cardiovascular disease, is increased in patients with PA compared with controls from the general population, particularly in patients aged >56 years, patients with preexisting cardiovascular comorbidities, and patients receiving low dose of a mineralocorticoid receptor antagonist.

Impact of autofluorescence for detection of parathyroid glands during thyroidectomy on postoperative parathyroid hormone levels: parallel multicentre randomized clinical trial.

BACKGROUND: Techniques for autofluorescence have been introduced to visualize the parathyroid glands during surgery and to reduce hypoparathyroidism after thyroidectomy. METHODS: This parallel multicentre RCT investigated the use of Fluobeam® LX to visualize the parathyroid glands by autofluorescence during total thyroidectomy compared with no use. There was no restriction on the indication for surgery. Patients were randomized 1 : 1 and were blinded to the group allocation. The hypothesis was that autofluorescence enables identification and protection of the parathyroid glands during thyroidectomy. The primary endpoint was the rate of low parathyroid hormone (PTH) levels the day after surgery. RESULTS: Some 535 patients were randomized, and 486 patients received an intervention according to the study protocol, 246 in the Fluobeam® LX group and 240 in the control group. Some 64 patients (26.0 per cent) in the Fluobeam® LX group and 77 (32.1 per cent) in the control group had low levels of PTH after thyroidectomy (P = 0.141; relative risk (RR) 0.81, 95 per cent c.i. 0.61 to 1.07). Subanalysis of 174 patients undergoing central lymph node clearance showed that 15 of 82 (18 per cent) in the Fluobeam® LX group and 31 of 92 (33 per cent) in the control group had low levels of PTH on postoperative day 1 (P = 0.021; RR 0.54, 0.31 to 0.93). More parathyroid glands were identified during operation in patients who had surgery with Fluobeam® LX, and fewer parathyroid glands in the surgical specimen on definitive histopathology. No specific harm related to the use of Fluobeam® LX was reported. CONCLUSION: The use of autofluorescence during thyroidectomy did not reduce the rate of low PTH levels on postoperative day 1 in the whole group of patients. It did, however, reduce the rate in a subgroup of patients. Registration number: NCT04509011 (http://www.clinicaltrials.gov).

Long-term outcome after surgical resection of non-high-risk gastrointestinal stromal tumours without adjuvant therapy.

BACKGROUND: Gastrointestinal stromal tumour (GIST) is the most common intra-abdominal sarcoma. Risk classification systems, commonly the modified National Institutes of Health consensus criteria, identify tumour properties relating to patient outcomes. However, owing to limited long-term evidence, most guidelines recommend up to 10-year follow-up for all risk groups except very low-risk GIST. METHODS: This retrospective multicentre study included patients who had complete resection of primary, non-metastatic GIST from three Scandinavian sarcoma centres: Gothenburg (2004-2020), Stockholm (2000-2019), and Oslo (2000-2017). Medical records were reviewed for clinical details regarding diagnosis, treatment, and follow-up, and recurrence-free and disease-specific survival evaluated. RESULTS: The total cohort consisted of 1213 patients with GIST. High-risk patients and those treated with tyrosine kinase inhibitors were excluded. The remaining 649 patients were included in the present analysis: 118 with very low-, 381 with low-, and 150 with intermediate-risk GISTs. Five-year recurrence-free survival rates were 100, 98.5, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.246). Disease-specific survival rates 10 years after surgery were 100, 98.4, and 100 per cent for the intermediate-, low-, and very low-risk groups respectively (P = 0.262). CONCLUSION: Patients with completely resected non-high-risk GISTs have an excellent long-term outcome, irrespective of risk group. Follow-up programmes to detect disease recurrences in these patients are probably not indicated.

Gastrointestinal stromal tumours (GISTs) originate from the muscle layer of the gastrointestinal tract. They are divided into risk groups according to size, location, and how quickly they grow. Patients with GIST, regardless of risk group, have been followed with imaging for several years after their tumour has been successfully removed with an operation. The aim of this study was to evaluate whether follow-up is necessary for patients in the lower-risk groups. Six hundred and forty-nine patients with GISTs from the lower-risk groups were followed for 5 years (median). Only 1.2 per cent of the patients experienced a recurrence of their cancer. It was concluded that patients with GIST in the lower-risk groups do not need follow-up with imaging after a successful operation.

Therapeutic outcomes with surgical and medical management for primary aldosteronism: protocol for a systematic review and meta-analysis.

INTRODUCTION: Treatment strategies for primary aldosteronism (PA) include unilateral adrenalectomy and medical treatment with mineralocorticoid receptor (MR) antagonists. Whether these two different treatment strategies are comparable in mitigating the detrimental effect of PA on outcomes is still debated. OBJECTIVES: The primary aim of this systematic review is to identify, appraise and synthesise existing literature comparing clinical outcomes after treatment in patients with PA. METHODS AND ANALYSIS: A systematic and comprehensive search will be performed using PubMed, Web of Science and EMBASE, for studies published until December 2022. Observational and interventional studies will be eligible for inclusion. The quality of observational studies will be assessed using the Newcastle-Ottawa Scale, while interventional studies will be assessed using the Cochrane Effective Practice Organization of Care tool. The collected evidence will be narratively synthesised. We will perform meta-analysis to pool estimates from studies considered to be homogeneous. Reporting of the systematic review and meta-analysis will be in accordance with the Meta-analysis of Observational Studies in Epidemiology Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. ETHICS AND DISSEMINATION: As this study is based solely on the published literature, no ethics approval is required. This review will aim to provide some estimates on outcomes, including survival, rates of clinical and biochemical control, cardiovascular and cerebrovascular events, as well as data on quality of life and renal function, in patients with PA treated surgically or with MR antagonists. The study findings will be presented at scientific meetings and will be published in an international peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42022362506.

Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2α correlate to an aggressive tumor phenotype. We show that HIF-2α localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2α expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.

[Many adrenal incidentalomas are not adequately evaluated - updated guidelines to improve follow-up are presented]. / Många binjureincidentalom får ingen adekvat utredning.

The use of cross-sectional imaging in Sweden has increased more than twofold in the last 20 years. Inadvertently discovered adrenal lesions, adrenal incidentalomas, are reported in about one per cent of abdominal investigations. The first Swedish guidelines for the management of adrenal incidentalomas were published in 1996 and have since then been regularly revised. Still, data indicate that less than half of patients receive adequate follow-up. Here we comment on the newly updated guidelines and briefly review the recommended clinical and radiological work-up.

Exposure to nonanoic acid alters small intestinal neuroendocrine tumor phenotype.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location. METHODS: Clinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology. RESULTS: Tumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology. CONCLUSION: Our results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.

Illness perspectives in patients with primary aldosteronism.

OBJECTIVE: The burden of symptoms and treatment in patients with primary aldosteronism (PA), as well as the patients' experience of the health care is sparsely studied. The objectives of this study were to describe symptoms considered to be the most troublesome by patients with PA, and to explore health related worries and expectations following treatment. METHODS: This was an explorative qualitative study where 25 patients with PA, diagnosed between 2017 and 2019, were included; 13 patients who had undergone adrenalectomy and 12 who were receiving medical treatment. Data was collected during six group interviews and analyzed using a thematic approach. RESULTS: Three main themes were identified: 1) Distress of the past, where the most important issues were struggle to receive a correct diagnosis, impaired well-being and the consumption of a large number of tablets, 2) Satisfaction after receiving a correct diagnosis, both in patients with unilateral and bilateral disease, but also dissatisfaction with lack of information about the disease, and 3) Future concerns, where worries about the long-term effects of PA on health in general dominated. CONCLUSIONS: Our findings illustrate several important issues related to PA where improvements in patient care are needed, including actions aiming at shortening the long diagnostic delay, a thorough information to the patients about the disease is of great importance, and that all patients with PA, regardless of treatment, would benefit from a structured long-term follow-up.

The incidence of insulinoma in Western Sweden between 2002 and 2019.

Background: Insulinoma is a rare pancreatic neuroendocrine neoplasm with an incidence of 0.7-4 cases per million/year. Because of its rarity, epidemiological studies on insulinoma are few and limited by small sample sizes. An increasing incidence of insulinoma has recently been suggested. The primary aim of this study was to investigate the incidence of insulinoma in the Västra Götaland Region (VGR) of Sweden. Secondary aims were to evaluate clinical characteristics, diagnostic workup, management and outcome in patients diagnosed with insulinoma. Methods: Medical records were reviewed for all patients in the VGR who had received an ICD-10 diagnosis code of a benign (D13.7) and/or a malignant (C25.4) tumor in the endocrine part of the pancreas, of hypoglycemia (E.161), and/or a code of a fasting test (AB011), from 2002-2019. Results: Forty-two patients with insulinoma were identified, 37 of whom (20 men) were residents in the VGR at the time of diagnosis, giving a mean annual incidence of 1.3 cases per million/year. The mean (±standard deviation) age at diagnosis was 56±18 years. Six of the 37 (16%) patients had metastatic insulinoma and 2 patients (5%) had a confirmed multiple endocrine neoplasia type 1 syndrome. At preoperative workup, computed tomography and endoscopic ultrasound detected an insulinoma in 28/36 (78%) and 21/21 (100%) cases, respectively. Conclusions: Insulinoma remains a rare tumor in the modern era. The recorded mean annual incidence of 1.3 cases per million/year is compatible with the reported incidence in Sweden during the 1980s. Our results do not support an increasing incidence of insulinoma.

Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine.

Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several tumors clustered together in a limited intestinal segment. SI-NET also shows an unusual absence of driver mutations explaining tumor initiation and metastatic spread. The evolutionary trajectories that underlie multifocal SI-NET lesions could provide insight into the underlying tumor biology, but this question remains unresolved. Here, we determine the complete genome sequences of 61 tumors and metastases from 11 patients with multifocal SI-NET, allowing for elucidation of phylogenetic relationships between tumors within single patients. Intra-individual comparisons revealed a lack of shared somatic single-nucleotide variants among the sampled intestinal lesions, supporting an independent clonal origin. Furthermore, in three of the patients, two independent tumors had metastasized. We conclude that primary multifocal SI-NETs generally arise from clonally independent cells, suggesting a contribution from a cancer-priming local factor.

Monitoring Circulating Tumor DNA During Surgical Treatment in Patients with Gastrointestinal Stromal Tumors.

The majority of patients diagnosed with advanced gastrointestinal stromal tumors (GISTs) are successfully treated with a combination of surgery and tyrosine kinase inhibitors (TKIs). However, it remains challenging to monitor treatment efficacy and identify relapse early. Here, we utilized a sequencing strategy based on molecular barcodes and developed a GIST-specific panel to monitor tumor-specific and TKI resistance mutations in cell-free DNA and applied the approach to patients undergoing surgical treatment. Thirty-two patients with GISTs were included, and 161 blood plasma samples were collected and analyzed at routine visits before and after surgery and at the beginning, during, and after surgery. Patients were included regardless of their risk category. Our GIST-specific sequencing approach allowed detection of tumor-specific mutations and TKI resistance mutations with mutant allele frequency < 0.1%. Circulating tumor DNA (ctDNA) was detected in at least one timepoint in nine of 32 patients, ranging from 0.04% to 93% in mutant allele frequency. High-risk patients were more often ctDNA positive than other risk groups (P < 0.05). Patients with detectable ctDNA also displayed higher tumor cell proliferation rates (P < 0.01) and larger tumor sizes (P < 0.01). All patients who were ctDNA positive during surgery became negative after surgery. Finally, in two patients who progressed on TKI treatment, we detected multiple resistance mutations. Our data show that ctDNA may become a clinically useful biomarker in monitoring treatment efficacy in patients with high-risk GISTs and can assist in treatment decision making.

Increasing Incidence of Primary Aldosteronism in Western Sweden During 3 Decades - Yet An Underdiagnosed Disorder.

CONTEXT: Primary aldosteronism (PA) is the most common cause of secondary hypertension. Yet, the incidence of PA in the general population has not been studied. OBJECTIVE: To estimate the incidence of PA in the general population. DESIGN AND METHODS: Patients who had received a diagnostic code for PA between 1987 and 2016 were identified in the Swedish National Patient Registry. Assessment of clinical and biochemical data was used to validate the diagnosis. The annual incidence of PA was calculated by using the number of inhabitants in the Västra Götaland County as a reference. RESULTS: Of 570 identified patients, 473 (83%) had confirmed PA. Eligible for the incidence analysis were 416 patients, 248 (60%) men and 168 (40%) women, diagnosed with PA between 1987 and 2016. The mean (± standard deviation) age at diagnosis was 56 ±â€…12 years. The median (interquartile range) annual incidence was 2 (1-2) cases per million between 1987 and 1996, 6 (4-9) cases per million between 1997 and 2006 and 17 (12-24) cases per million between 2007 and 2016. At the end of the study (December 31, 2016), 386 patients with confirmed PA were alive and living in the Västra Götaland County, giving a prevalence of 231 cases per million (0.022%). CONCLUSIONS: Despite increasing incidence, the proportion of patients identified with PA is lower than expected. Given the serious consequences of untreated PA, the noticeably low prevalence at the end of the study stresses the need to increase the awareness of PA among health care providers.

Adrenal Venous Sampling in Young Patients with Primary Aldosteronism. Extravagance or Irreplaceable?

CONTEXT: Current clinical guidelines suggest that adrenal venous sampling (AVS) may not be mandatory in young patients with primary aldosteronism (PA) and a solitary adrenal adenoma on imaging. OBJECTIVE: The aim of this study was to further elucidate whether conventional imaging alone is sufficient to distinguish unilateral from bilateral PA among patients aged 40 years or younger. METHODS: This was a retrospective study where data from 45 patients with PA, aged between 26 and 40 years, who underwent successful AVS between 2005 and 2019, were analyzed. Results concerning laterality on imaging studies and AVS were recorded. Outcome in surgically treated patients was assessed according to the Primary Aldosteronism Surgical Outcomes criteria. RESULTS: In 4 of 25 patients with unilateral aldosterone production according to AVS, computed tomography inaccurately suggested bilateral disease. Following unilateral adrenalectomy, all 4 patients showed complete clinical success. Five of 20 patients with bilateral aldosterone production according to AVS had a solitary adrenal nodule (8-19 mm) on imaging. Two of these 5 patients were treated with unilateral adrenalectomy, neither having complete biochemical and/or clinical success postoperatively. Two of 16 patients younger than 35 years had discordant results, 1 with unilateral and 1 with bilateral aldosterone production, according to AVS. CONCLUSION: Imaging studies inaccurately predicted laterality in a significant number of young patients with PA. In contrast to current clinical guidelines, our results support AVS for subtype evaluation in young adults with PA, including patients 35 years or younger.

Primary Adrenal Leiomyosarcoma: Clinical, Radiological, and Histopathological Characteristics.

Primary adrenal leiomyosarcoma (PAL) is a rare, high-grade proliferating mesenchymal tumor with a considerable risk of metastasis, deriving from the smooth muscle wall of a central adrenal vein, or its tributaries. Roughly 40 patients with PAL have been reported in the literature. Herein, we present 3 patients with incidentally discovered PAL, along with an overview of the current knowledge on the clinical, radiological, and histopathological characteristics of PAL.

MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression.

Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors.

Outcomes After Surgery for Unilateral Dominant Primary Aldosteronism in Sweden.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension. Surgery is the mainstay of treatment for unilateral dominant PA, but reported cure rates varies. The aim of the present study was to investigate contemporary follow-up practices and cure rates after surgery for PA in Sweden. METHODS: Patients operated for PA and registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) 2009-2015 were identified. Patient data were extracted, and follow-up data (1-24 months) was recorded. Doses of antihypertensive medication and potassium supplementation were calculated using defined daily doses (DDD), and the Primary Aldosteronism Surgical Outcome (PASO) criteria were used to evaluate outcomes. RESULTS: Of 190 registered patients, 171 (47% female, mean age 53 years, median follow-up 3.7 months) were available for analysis. In 75 patients (44%), missing data precluded evaluation of biochemical cure according to the PASO criteria. Minimal invasive approach was used in 168/171 patients (98%). Complication rate (Clavien-Dindo >3a) was 3%. No mortality was registered. Pre/postoperatively 98/66% used antihypertensives (mean DDD 3.7/1.5). 89/2% had potassium supplementation (mean DDD 2.0/0) before/after surgery. Complete/partial biochemical and clinical success according to the PASO criteria were achieved in 92/7% and 34/60%, respectively. CONCLUSION: In this study, reflecting contemporary clinical practice in Sweden complete/partial biochemical and clinical success after surgery for PA was 92/7% and 34/60%. Evaluation of biochemical cure was hampered by lack of uniform reporting of relevant outcome measures. We suggest mandatory reporting of surgical outcomes using the PASO criteria for all units performing surgery for PA.