The Endocrine Surgical Research Group runs studies of genetics, diagnosis and treatment of endocrine tumours, in order to identify genes involved in tumour development and progression, and to ultimately provide possibilities for new treatment. We have always included translational studies in our work. In clinical studies genetic changes are related to the disease course of individual tumours, with the overall aim to improve diagnosis and treatment in patients with endocrine tumour disease. We are also studying indications for surgery, survival benefits and optimization of surgery from different perspectives.
- Adrenomedullary tumors - Pheochromocytoma
- Adrenocortical tumours
- Small intestinal Neuroendocrine tumours (SI-NET; formerly midgut carcinoids)
- Pancreatic NETs
- Healthcare research
Endocrine tumours are of special interest in tumour biology because of a common extended disease course, and often presence of only few specific genetic changes, which can be related to variable tumour biology. For many endocrine tumours histopathology can often not distinguish tumours with more malignant biological features, and there is a general hope that genetic differences will provide better means of discrimination. Genetic studies are expected to become of great importance for the clinical management by predicting prognosis, and genetic defects may be used as targets for new treatment. The overall aim of the studies is to identify tumour genes and other prognostic markers of importance for the development and progression of endocrine tumours, reveal gene changes with new technology, and investigate new possibilities of treatment against tumour progression.
Other research, more clinical, lines are the studies of treatment of liver metastases in small intestinal as well as pancreatic NETs, to pinpoint the surgical indication and the efficacy of surgical treatment. Also non-surgical treatment is scrutinized as an option. In thyroid surgery postoperative hypoparathyroidism has been displayed as a far more important and frequently occurring complication than previously expected. The novel analogue 18F-CETO for PET has been developed by us, and is now established for adrenocortical disease. Further studies with 18F-CETO-PET/CT is ongoing for further clarification of its role especially in adrenocortical cancer and primary aldosteronism.
As an overall resource we have access to >3000 specimens and blood samples from patients operated for endocrine tumours during >20 years. The samples, stored at Uppsala Biobank, have being used in many previous studies and is a valuable and important source in our studies.
Studies of pheochromocytoma and paraganglioma have used the latest DNA sequencing techniques to characterize polymorphisms, mutations, deletions and insertions in DNA, from both benign and malignant tumours. We have previously developed 11C-HED and have clarified the efficacy for this tracer in PET. Also, the use of Lutetium as therapy has been scrutinized.
In a study performed in collaborations with Yale University, and which was published in Science in 2011, breakthrough of genetic knowledge of adrenal tumours was initiated. A mutation in KCNJ5, an ion channel, was noted in approximately 45% of tumours. Further, we have revealed mutations in CACNA1D in a subset of these tumours as well, and in the cortisol-producing tumours in PRKACA. We are currently looking at differences between benign and malignant adrenal tumours, also on the epigenetic level.
The most common cause for secondary hypertension is primary aldosteronism, and to find proper prevalence we have screened 1200 individuals with hypertension in primary care. We found that 4,5% of this cohort have primary aldosteronism, which now have given the patients possibility to targeted treatment (surgery or medical treatment). We are aiming for identification of novel biomarkers for this disease, in peptides and in microRNA, as well as the pattern of steroids. Moreover, we are with individuals from this cohort also evaluating the role of 18F-CETO-PET/CT in the diagnostic work-up for primary aldosteronism.
Malignant adrenocortical tumours (ACC) are being investigated for molecular genetic signatures, as well as development of new mutations with time, and within different areas in the same tumour.
Our parathyroid studies are currently focused on identifying differences between parathyroid adenoma and carcinoma. We have noted that derangements in the structure or function of beta cathenin, HIC1, APC, EZH2 may be important, as well as differences in methylation or hydromethylation in the parathyroid tissue.
SI-NETs have been studied with several different methods in order to identify molecular derangements to understand the underlying mechanisms for tumour development. Initially, we identified the presence of a suspect tumour suppressor gene for SI-NETs on chromosome 18q. Further studies have utilized SNP and expression microarrays, sequencing, SNV analyses, proximity extension assay (OLINKs method) and methylation arrays to reveal characteristics for more or less aggressive tumours. We have identified bad prognostic signs in presence of peritoneal carcinosis. Whole genome sequencing have been performed, and currently single cell and long-read sequencing are being analyzed in order to identify additional derangements, especially on chromosome 18q. We are investigating how different treatments affect SI-NET cell lines in vitro and in vivo. We have been able to demonstrate epigenetic derangements and has shown that metformin reduces growth in SI-NET cell lines and are currently investigating this in animal models.
In a prospective study we have compared classical surgical techniques with a novel handport-assisted laparoscopic method. We have found at least non-inferiority using laparoscopy.
Our previous report regarding avoiding surgery if not R0 can be reached (stadium 4) in patients without abdominal symptoms has been followed up. We note that the among the not operated patients there are extremely few that need surgery, thus supporting our previous conclusion that this group of patients do not need surgery.
Several previous studies have investigated gene changes associated with pancreatic NETs. In a collaborative effort with Yale University we showed early that mutations in YY1 was present in approximately 40% of insulinomas. Further work includes characterization of DAXX mutations and expression. Further analyses of genetic derangements in multiple endocrine neoplasia type 1 (MEN1) are also performed. A local work within the Centre of Excellence is investigating the genetic evolution of pancreatic NETs, as well as genetic effects of chemotherapy treatment.
We have studied the effect of liver surgery for metastases of pancreatic NET, and the overall survival benefit in case of metastasized disease.
We have a collaboration with the research group for Healthcare regarding life quality, and outcome of surgery of neuroendocrine tumours.
Members of the group 2023
Per Hellman, Professor, Endocrine surgery
Peter Stålberg, Professor, Endocrine surgery
Olov Norlén, Consultant, Associate Professor
Matilda Annebäck, MD, PhD
Josefin Kjaer, MD, PhD
Tobias Åkerström, MD, PhD
Samuel Backman, MD, PhD
Elham Barazeghi, PhD
Branislav Klimacek (SI-NET)
Nikita Mahknov (Primary aldosteronism)
Fredrik Axling ((molecular genetic studies of NET)
Frida Olsson (healthcare research)
Collaboration is continuously running with other groups within Academic Hospital: Uppsala Centre of Excellence for Endocrine Tumors.
Collaboration is also ongoing in Sweden with Sahlgrenska and internationally with Groeningen, Harvard in Boston, Melbourne, Oxford and Sydney.
The last years publikations are depicted in the Institutions Research Report Annual report. Earlier and later articles can be searched in the database for publikations DiVA (Digitala Vetenskapliga Arkivet – Digital scientific archive).
Some selected publications:
- Daskalakis K, Karakatsanis A, Hessman O, Stuart HC, Welin S, Tiensuu Janson E, et al. Association of a Prophylactic surgical approach to Stage IV Small Intestinal Neuroendocrine Tumors with Survival. JAMA Oncology [Internet]. 2018;4(2):183–9.
- Backman S, Bajic D, Crona J, Hellman P, Skogseid B, Stålberg P. Whole genome sequencing of apparently mutation-negative MEN1 patients. European Journal of Endocrinology [Internet]. 2020;182(1):35–45.
- Annebäck M, McHale Sjödin E, Hellman P, Stålberg P, Norlén O. Preoperative prophylactic active vitamin D to streamline total thyroidectomy. BJS Open [Internet]. 2022;6(3).
- Silins I, Sundin A, Lubberink M, O’Sullivan L, Gurnell M, Aigbirhio F, et al. First-in-human evaluation of [18F]CETO : a novel tracer for adrenocortical tumours. European Journal of Nuclear Medicine and Molecular Imaging [Internet]. 2023;50(2):398–409.
- Kjaer J, Clancy TE, Thornell A, Andersson N, Hellman P, Crona J, et al. Benefit of Primary Tumor Resection in Stage IV, Grade 1 and 2, Pancreatic Neuroendocrine Tumors : A Propensity-Score Matched Cohort Study. Annals of Surgery Open [Internet]. 2022;3(1).
- Barazeghi E, Hellman P, Norlén O, Westin G, Stålberg P. EZH2 presents a therapeutic target for neuroendocrine tumors of the small intestine. Scientific Reports [Internet]. 2021;11.
- Backman S, Åkerström T, Maharjan R, Cupisti K, Willenberg HS, Hellman P, et al. RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas. Scientific Reports [Internet]. 2019;9.
- Annebäck M, Hedberg J, Almquist M, Stålberg P, Norlén O. Risk of Permanent Hypoparathyroidism After Total Thyroidectomy for Benign Disease : A Nationwide Population-based Cohort Study From Sweden. Annals of Surgery [Internet]. 2021;274(6):e1202–8.
- Kjaer J, Smith S, Hellman P, Stålberg P, Crona J, Welin S, et al. Overall Survival in Patients with Stage IV Pan-NET Eligible for Liver Transplantation. World Journal of Surgery [Internet]. 2023;47:340–7.