Dopamine in platelets in patients with paragangliomas/pheochromocytoma

Pheochromocytoma, sympathetic PGL and parasympathetic HNPGL are rare
neuro-endocrine tumors that can synthesize and secrete catecholamines derived
from neural-crest-derived chromaffin cells. The term pheochromocytoma is used
for intra-adrenal PGLs, whereas similar but extra-adrenal tumors are named
(extra adrenal) PGLs. Parasympathetic PGLs arise near the parasympathetic
nerves in the head and neck and mediastinal region, sympathetic PGLs are
symmetrically situated along the sympathetic trunk.
Pheochromocytoma and PGLs occur sporadically and in several hereditary tumor
syndromes, including the pheochromocytoma-paraganglioma syndrome. This syndrome
is caused by germline mutations in succinate dehydrogenase (SDH) subunit B
(SDHB), subunit C (SDHC) or subunit D (SDHD) genes. About 10-30% of apparently
sporadic pheochromocytomas and PGLs harbour germline SDH-gene mutations.
Patients with SDHB and SDHD gene mutations have been shown to be at risk of
development of multiple PGLs in the head and neck, thorax, and abdomen.
Pheochromocytomas and PGLs can also occur in other familiar/hereditary
syndromes. Germline mutations for these familiar syndromes may occur in the von
Hippel-Lindau (VHL) gene which causes von Hippel-Lindau syndrome; the RET gene
leading to multiple endocrine neoplasia (MEN) type 2 and the neurofibromatosis
type 1 (NF1) gene, which is associated with von Recklinghausen*s disease.
Measurement of the plasma and urinary metabolites of catecholamines,
(nor)metanephrine and 3-metoxytyramine (3-MT), is the cornerstone of for the
diagnosis of a pheochromocytoma or a sympathetic PGL. However, parasympathetic
HNPGL rarely secrete catecholamines. Therefore, it is difficult to determine
tumor activity biochemically and extensive imaging is necessary in the
diagnostic work-up of these patients. Recently we and others have shown that
dopamine secretion, measured as 3-MT in urine, can be demonstrated in 19-23% of
patients with HNPGL. In these studies the urine 3-MT concentration was the most
sensitive method to measure dopamine production. Measurement of 3-MT and
(nor)metanephrine in urine are however affected by catecholamine-rich products
in the diet, which increases the possibility of false-positive results.
Increased 3-MT may especially be expected in patients with SDHB and SDHD
mutations.
The biochemical diagnosis of HNPGL could be improved if dopamine could be
measured in a more sensitive way.
Free dopamine, secreted by the PGL or pheochromocytomas, is taken up from the
body circulation by platelets through the dopamine transporter (DAT), and
stored inside the platelets. The lifespan of platelets in the circulation is
8-10 days. In this way, platelet levels of dopamine reflect the whole 10-day
dopamine metabolism.
The platelet level of dopamine could be a relatively new diagnostic parameter
and has not been used before in patients with PGLs or pheochromocytomas. The
platelet level of dopamine has been studied in patients with migraine and
cluster headache. Plasma levels of dopamine in platelets in patients with
migraine and cluster headache were higher than normal controls.
If the platelet level of dopamine is proven to be a sensitive marker for the
presence of HNPGL, this is expected to be clinically useful as a tumor marker
for early detection of (recurrent) disease in carriers of a mutation
predisposing to PGL and pheochromocytoma, especially in patients with SDH
mutations. Furthermore it would be interesting to determine dopamine in
platelets before and after curative surgery of PGL and pheochromocytoma.

The purpose of the study is to determine the sensitivity of dopamine platelets
levels in patients with clinically suspected or diagnosed HNPGL, abdominal PGL,
and pheochromocytoma.

Primary Objective:
The sensitivity of dopamine levels in platelets in patients with clinically
suspected and/or diagnosed head HNPGL.

Secondary Objective:
The value of dopamine level in platelets in patients with PGL and
pheochromocytoma.

This study is a prospective single center study.
Patients with PGLs and pheochromocytomas known at the departments of Ear Nose
and Throat (ENT) and Endocrinology at the University Medical Centre Groningen
are eligible for inclusion, as well as patients who are suspected of a PGL or
pheochromocytoma. During routine venapuncture an additional blood volume of 20
ml is drawn. This additional blood volume will be stored at -80 0C until
processing in the department of laboratory medicine.

The platelet level of dopamine is a relatively new diagnostic parameter and has
not been used before in patients with PGLs. If dopamine platelet levels is a
sensitive marker in patients with HNPGLs, it could be a useful marker for
screening and follow-up in patients. Participating patients are not exposed to
any additional risks, as the extra blood volume needed for this study is drawn
during a venapuncture performed for routine blood testing.

Because of the low risk profile of this investigation, the judging Medical
Ethical Committee of the Universitair Medisch Centrum of Groningen has decided
that there will be a release of the insurance obligation as intended in art. 4
lid 1 of the decision obligatory assurance in medical research with humans.