Biomarkers in pheochromocytomas and paragangliomas

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

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.
Original languageEnglish
Awarding Institution
  • University of Helsinki
Supervisors/Advisors
  • Arola, Johanna, Supervisor
  • Haglund, Caj, Supervisor
  • Salmenkivi, Kaisa , Supervisor
Award date21 Dec 2018
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-4750-9
Electronic ISBNs978-951-51-4751-6
Publication statusPublished - 2018
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • Paraganglioma
  • +diagnosis
  • +genetics
  • Pheochromocytoma
  • Thyroid Neoplasms
  • Biomarkers
  • Neoplasm Metastasis
  • Biomarkers, Tumor
  • ELAV-Like Protein 1
  • Receptors, Somatostatin
  • Polysaccharides
  • Adrenal Medulla
  • Immunohistochemistry
  • +methods
  • Cyclooxygenase 2
  • Succinate Dehydrogenase
  • Neoplastic Processes
  • 3111 Biomedicine

Cite this

@phdthesis{27a7a1193e544cd9a76a473eefb1bfe4,
title = "Biomarkers in pheochromocytomas and paragangliomas",
abstract = "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.",
keywords = "Paraganglioma, +diagnosis, +genetics, Pheochromocytoma, Thyroid Neoplasms, Biomarkers, Neoplasm Metastasis, Biomarkers, Tumor, ELAV-Like Protein 1, Receptors, Somatostatin, Polysaccharides, Adrenal Medulla, Immunohistochemistry, +methods, Cyclooxygenase 2, Succinate Dehydrogenase, Neoplastic Processes, 3111 Biomedicine",
author = "Helena Leijon",
note = "M1 - 82 s. + liitteet",
year = "2018",
language = "English",
isbn = "978-951-51-4750-9",
publisher = "[H. Leijon]",
address = "Finland",
school = "University of Helsinki",

}

Leijon, H 2018, 'Biomarkers in pheochromocytomas and paragangliomas', University of Helsinki, Helsinki.

Biomarkers in pheochromocytomas and paragangliomas. / Leijon, Helena.

Helsinki : [H. Leijon], 2018. 82 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Biomarkers in pheochromocytomas and paragangliomas

AU - Leijon, Helena

N1 - M1 - 82 s. + liitteet

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Paraganglioma

KW - +diagnosis

KW - +genetics

KW - Pheochromocytoma

KW - Thyroid Neoplasms

KW - Biomarkers

KW - Neoplasm Metastasis

KW - Biomarkers, Tumor

KW - ELAV-Like Protein 1

KW - Receptors, Somatostatin

KW - Polysaccharides

KW - Adrenal Medulla

KW - Immunohistochemistry

KW - +methods

KW - Cyclooxygenase 2

KW - Succinate Dehydrogenase

KW - Neoplastic Processes

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-4750-9

PB - [H. Leijon]

CY - Helsinki

ER -