Diagnosis of Pheochromocytoma

Pheochromocytomas and paragangliomas are rare but clinically important chromaffin cell tumors
that typically arise from the adrenal gland or from extra-adrenal paraganglia, respectively
and constitute a surgically correctable cause of chronic hypertension. The clinical features
and consequences of pheochromocytoma/paraganglioma result from the release of catecholamines
(e.g., norepinephrine and epinephrine) by the tumor. If a pheochromocytoma/paraganglioma is
undetected, stimuli that normally would not pose a hazard, such as surgery, childbirth, or
general anesthesia, can evoke catecholamine secretion by the tumor, with clinically
significant and even catastrophic outcomes. The diagnosis of pheochromocytoma/paraganglioma
and its localization can be challenging, because measurements of plasma levels or urinary
excretion of catecholamines and their metabolites as well as radio-iodinated
metaiodobenzylguanidine (MIBG) scanning can yield false-positive/negative results in patients
harboring the tumor. Computed tomography (CT) and magnetic resonance imaging (MRI) lack
sufficient specificity. The molecular mechanisms by which genotypic changes predispose to the
development of pheochromocytoma/paraganglioma remain unknown, even in patients with
identified mutations. Moreover, pheochromocytomas/paragangliomas in patients with hereditary
predispositions differ in terms of their growth, malignant potential, catecholamine
phenotype, responses to standard screening tests, such as the clonidine suppression test,
various imaging modalities, and different therapeutic options. This protocol focuses on
developmental, molecular, genetic, epigenetic, proteomic, metabolomics, and other types of
studies to elucidate the bases for predisposition to develop pheochromocytomas/paragangliomas
and for expression of different neurochemical phenotypes and malignant potentials including
therapeutic responses. Furthermore, this protocol will also use new imaging approaches, for
example [(18)F]-6F-dopamine ([(18)F]-6F-DA), [(18)F]-L-3,4-dihydroxyphenylalanine
([(18F)]-DOPA), and [(68)Ga]-DOTA-Tyr-octreotate ([(68)Ga]-DOTATATE) positron emission
tomography (PET)/CT, as well as PET/MRI scanning, and dynamic contrast-enhanced MRI.
Additionally, new biochemical diagnostic criteria exist for the measurement of plasma
metanephrines and methoxytyramine for the clinical diagnosis and localization of these
tumors. This protocol will also evaluate the benefits of histone deacetylase inhibitors (e.g.
romidepsin) pretreatment for uptake enhancement of [(123/131)I]-MIBG in
pheochromocytoma/paraganglioma tumors.

- INCLUSION CRITERIA:

- Patients are adults or children of any age with known, sporadic or familial PHEO/PGL,
on the basis of one or more of the following:

1. High levels of blood or urinary catecholamines, metanephrines, methoxytyramine or
chromogranin A.

2. Highly suspected presence of PHEO/PGL based on imaging studies, even with normal
biochemistry.

3. Personal or family history of PHEO/PGL or genetic mutations known to predispose
individuals to develop PHEO/PGL.

- Normal volunteers over the age of 18 years, including those with normal or high blood
pressure, are to be used for reference values regarding biochemical and imaging
diagnosis of PHEO/PGL. Normal volunteers with high blood pressure can be on blood
pressure medication.

- Patients and normal volunteers can be studied to provide blood/urine samples for
biochemical, proteomic, and/or genetic and epigenetic analysis.

- Signed informed consent is required.

- Patients must be willing to return to NIH for follow-up evaluation.

- Patients must have an outside general practitioner or endocrinologist. Patients with
metastatic disease must also have an outside oncologist.

- Patients with PHEO/PGL will be accepted through clinician or self- referrals.

EXCLUSION CRITERIA:

Potential patients will be excluded on the basis of one or more of the following:

1. Pregnant (based on a pregnancy test done either outside the NIH or at the NIH) or
breastfeeding women

2. Severe cardiac dysfunction

3. Currently on dialysis

-A pregnancy test is performed in women of childbearing age (up to age 55). If after
enrollment to this protocol, a patient is found to have a positive pregnancy test, her
participation in this protocol will be terminated..

- Research scans are contraindicated in patients with proven myelodysplastic
syndrome.

- Patients who are not willing to return to the NIH (e.g., after surgery or an
initial evaluation) for more than 2 years may be removed from the protocol.

- Pregnant and lactating women will not be included in the protocol because their
participation as a demographic is not essential to this study. The information we
are seeking can be acquired from a cohort of non-pregnant patients. The exclusion
of pregnant women does not preclude these patients from receiving appropriate
care and management from an outside facility.

SPECIFIC ELIGIBILITY CRITERIA FOR IMAGING STUDIES WITHIN OUR PROTOCOL:

-In adult patients:

--Imaging studies are not done in patients that have the following exclusion criteria:

---Pregnant and lactating women,

---Patients with a body weight of (Bullet)400 pounds due to weight limitations of
PET/CT/MRI scanners or patients who are not able to enter the bore of PET/CT/MRI
scanners due to BMI,

Inability to lie still for the entire imaging time (e.g. cough, severe arthritis,
etc.),

---Inability to complete the needed investigational and standard-of-care imaging
examinations due to other reasons (severe claustrophobia, radiation phobia, etc.),

---Any additional medical conditions, serious illness, or other extenuating
circumstance that, in the opinion of the Principal Investigator, may significantly
interfere with study compliance.

---Additionally, DCE-MRI is not done in patients with acute or chronic renal
insufficiency since gadolinium chelate injection is contraindicated in those patients.
In patients where DCE-MRI is considered, a creatinine clearance measurement is
performed as a clinically indicated test by the Department of Laboratory Medicine at
the NIH Clinical Center. Patients with impaired kidney function will not undergo
DCE-MRI. DCE-MRI is also not done in patients with severe claustrophobia or who have
iron or metal in the MRI scan site, in patients with pacemakers or defibrillators, or
in patients with an allergy to gadolinium. Very rarely, gadolinium at the site of
injection or the dosed limb can cause skin and soft tissue necrosis, thrombosis,
fasciitis, and compartment syndrome requiring surgical intervention.

-In pediatric patients:

--Inclusion criteria for research PET imaging in children

---Children over 10 years old with very high suspicion of sporadic or familial
pheochromocytoma/paraganglioma (e.g. the presence of new onset of hypertension or
hypertensive episodes, sweating, headaches, pallor, palpitations, drug resistant
hypertension, etc.) family history of pheochromocytoma/paraganglioma or genetic
mutations known to predispose individuals to develop these tumors, or the presence of
a tumor on conventional imaging /ultrasounds, CT, MRI.

- Children must give written informed assent and be willing to return to the NIH
for follow-up.

- Female patients of childbearing age must have a negative pregnancy test on the
day of the enrollment into this protocol and within 24 hours of any treatment or
test involving radioactivity or radiation exposure. They should be abstinent or
use appropriate contraception while taking part in the study, which involves
radiation.

--Exclusion criteria for research PET imaging in children

- Children of less than 10 years of age,

- Children with impaired mental capacity that precludes informed assent,

- Pregnant or lactating female adolescents,

- Inability to lie still for the entire imaging time (e.g. cough, turbulent
children, severe claustrophobia, etc.).