Pheochromocytomas (PHEOs) derived from adrenal medulla and paragangliomas (PGLs) from sympathetic or parasympathetic paraganglia are rare neuroendocrine tumors. Incidence of PHEOs and PGLs is between 0.4–9.5 cases per one million people per year. In Finland about 10–15 PHEOs are diagnosed per year, but the incidence is rising. PHEOs and sympathetic PGLs can secrete catecholamines, often in bouts, which makes the symptoms associated with these tumors very diverse, with high blood pressure being the leading symptom. During recent years, knowledge of the variable genetic background and pathogenesis of PGLs and PHEOs has increased, and about 30-40% of these tumors are known to be hereditary. However, prognosis and aggressiveness of an individual tumor cannot be unequivocally predicted histologically or with any biomarkers. The aim of this thesis was to find biomarkers in PHEOs and PGLs for diagnostic, prognostic, and predictive purposes. The study cohort consisted of 153 consecutive PHEOs or PGLs operated from 147 patients during the years 1973–2009 at Helsinki University Hospital. Tissue microarray blocks were constructed for immunohistochemistry studies. Matrix-assisted laser desorption/ionization time of flight mass spectrometric profiling of 16 tissue samples was used to analyze N-glycan structures in eight metastasized and eight nonmetastasized tumors. In addition, five thyroid PGLs originating from the population-based European-American-Head-and-Neck-Paraganglioma-Registry (European-American-HNPGL-Registry, Freiburg, Germany) were investigated. Metastasized PHEOs and PGLs expressed significantly more intracytoplasmic human antigen R (HuR) protein immunohistochemically than nonmetastasized tumors. The metastatic potential was also associated with higher proliferation and tumor necrosis. Five somatostatin receptors (SSTR1–5) showed individual and varying SSTR profiles in PHEOs and PGLs. The most abundant SSTRs were SSTR2 and SSTR3. Between metastatic PHEOs and PGLs the SSTR2 expression varied – all PGLs were strongly SSTR2 positive, while most PHEOs were negative. The N-glycan profile differed depending on the metastatic status of the tumor. Metastasized tumors expressed more fucosylation and complex fucosylation in their N-glycans. Based on different N-glycan profiles, metastatic and nonmetastatic tumors could be separated in principal component analysis. Extremely rare thyroid PGLs showed a strong association with succinate dehydrogenase (SDH) mutation. Of five patients with thyroid PGL, two had SDHB mutation and two SDHA mutation. In our Finnish cohort, 10% of PHEO and PGL patients had SDHB mutation and 40% of these a metastatic disease. In conclusion, intracytoplasmic HuR is increased in most metastatic PHEOs and PGLs and can be used in the panel of prognostic markers in these tumors. HuR may have a role in malignant transformation. PHEOs and PGLs have individual variable SSTR1–5 profiles. Investigating the SSTR1–5 profile in PHEOs and PGLs can be beneficial in choosing somatostatin analog based imaging and therapy. Metastasized and nonmetastasized PHEOs and PGLs have differences in N-glycans. Those N-glycans, associated with aggressive disease, may possibly be used in the future as prognostic biomarkers. PHEOs and PGLs have a strong genetic background, and genetic testing is recommended for PHEO and PGL patients.
|Tilldelningsdatum||21 dec 2018|
|Status||Publicerad - 2018|
|MoE-publikationstyp||G5 Doktorsavhandling (artikel)|
Bibliografisk informationM1 - 82 s. + liitteet
- 3111 Biomedicinska vetenskaper