CLINICAL PROBLEM SOLVING

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• CLINICAL PROBLEM SOLVING
• Current Approaches and Recommended Algorithm
  for the Diagnostic Localization of
  Pheochromocytoma
• The Journal of Clinical Endocrinology
  Metabolism
• February 2004 , Vol. 89, No. 2 479-491
• 93-2-25 ?? ???

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Introduction

• PHEOCHROMOCYTOMAS (PHEO)
• (1) catecholamine-producing tumors that arise
  from chromaffin cells
• (2) mostly situated within the adrenal
  medulla, although in about 923 of cases, tumors
  develop from extraadrenal chromaffin tissue
  (adjacent to sympathetic ganglia of the neck,
  mediastinum, abdomen, and pelvis) and are often
  referred to as paragangliomas)

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• In children, multifocal and extraadrenal PHEO are
  found in up to 3043 of cases
• The prevalence of malignancy in sporadic adrenal
  PHEO is 9, about 10 of patients with PHEO
  present with metastatic disease
• No absolute clinical, imaging, or laboratory
  criteria to predict malignancy and clinical
  course of PHEO

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• Localization of PHEO, at least two imaging
  modalities
• (1) Anatomical imaging (CT/MRI)
• (2) Functional imaging
• Enabled by the presence of the noradrenergic
  transporter system on PHEO cells
• Include 123I- or 131IMIBG
  scintigraphy
• 6-18Ffluorodopamine (18FDA),
  18Fdihydroxyphenylalanine (18FDOPA),
  11Chydroxyephedrine, and 11Cepinephrine
  positron emission tomography (PET)
• MIBG Metaiodobenzylguanidine

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• Functional imaging modalities
• (1) confirm that a tumor is a PHEO or can
  lead to further diagnostic work-up
• (2) rule out metastatic disease
• may be failure of localization of malignant
  PHEO, 18F fluorodeoxyglucose (18FFDG) PET
  scanning or somatostatin receptor scintigraphy
  (Octreoscan) may be required as the next step

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Anatomical imaging

• CT and MRI are common initial imaging modalities
• PHEO that secrete only epinephrine have high
  plasma or urinary epinephrine or metanephrine
  levels, and almost always have an adrenal tumor
• Norepinephine and normetanephrine can be
  secreted by PHEO localized both within and
  outside the adrenal gland (paraspinous area)

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CT imaging

• Adrenal PHEO of 0.51.0 cm or larger or
  metastatic PHEO at least 1.02.0 cm in size can
  be detected by CT ( 2 to 5mm section)
• Adenoma homogenous ,less than 10 (HU)
• PHEO (1) usually homogeneous, with soft
  tissue density (4050 HU)
• (2) Larger PHEO tumors may
  undergo hemorrhage and can be inhomogeneous, and
  areas of low density can be seen after tumor
  necrosis

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• Extraadrenal PHEO are located close to the
  inferior vena cava and the abdominal aorta and
  alongside the sympathetic ganglia and
  Zuckerkandls organ (710), between the inferior
  mesenteric artery and the aortic bifurcation, in
  the mediastinum (1), or near the urinary bladder
  (1)

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• Traditionally, ?- and possibly also ß-adrenergic
  receptor antagonist administration is advised for
  patients with biochemically proven PHEO to safely
  give ionic monomeric iv contrast for enhanced CT
  examination .
• However, no rise in plasma catecholamines was
  observed in 10 patients with PHEO who were given
  ioexol, a nonionic contrast medium

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MRI imaging

• MRI T1 sequences, PHEO have a signal like those
  of the liver, kidney, and muscle
• Presence of fat in benign adenomas and the
  absence of fat in PHEO.
• Hypervascularity of PHEO makes them appear
  characteristically bright, with a high signal on
  T2 sequence

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A, Abdominal CT of a 44-yr-old man with MEN 2A.
Bilateral adrenal PHEOs (56 cm in maximum
diameter) are evident (arrows) the lesion in the
left adrenal appears to be bilobed. B, Abdominal
T2-weighted MRI scans of the same patient. The
bilateral adrenal PHEOs show a characteristically
high signal (arrows). Both tumors were
hemorrhagic, and the left PHEO was cystic, which
explains their relative inhomogeneity of
appearance.
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CT-MRI-U/S

• Sensitivity
• CT MRI U/S
• 85-94(adrenal) 93-100
  83-89
• 90 (extraadrenal) 90
• Specificity
• 29-50 100/50(excluding PHEO)
• 
  60

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Functional imaging

• Adrenal masses are present in about 59 of the
  general population, about 6.5 of adrenal masses
  are PHEO
• Nuclear medicine imaging is also important in
  localizing PHEO in patients in whom anatomic
  imaging is negative and in the detection of
  metastatic lesions

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MIBG imaging MIBG Metaiodobenzylguanidine

• MIBG is an aralkylguanidine that resembles
  norepinephrine. Radioactive labeling is performed
  with the iodine isotopes 131 I and 123 I at the
  meta-position of the benzoic ring
• 131 I has a long half-life (8.2 d), 123 I has
  a shorter half-life (13 h)
• Influenced by medications such as certain nasal
  decongestants, antihypertensives,
  antidepressants, and antipsychotics

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• The amount of free 131I in 131I MIBG is less
  than 5, and after administration, MIBG releases
  a further small percentage (3) of free 131I
• Prevent thyroid damage, patients should take a
  saturated solution of potassium iodide (100 mg
  twice a day) or potassium perchlorate should be
  given (200300 mg twice a day) . 1 d before
  receives MIBG, 4 or 7 d after administration of
  123I- or 131IMIBG

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• Scintigraphy is performed after 24 h
• 123IMIBG uptake (in as many as 3275 of
  patients after 24 h) in normal adrenal medulla
  while 16 in 131 I
• 131IMIBG scintigraphy has a sensitivity ranging
  from 7790 and a high specificity (95100) for
  PHEO

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PET imaging

• Performed within minutes or hours after the
  injection of short-lived positron-emitting agents
  
• 18FFDG, 11Chydroxyephedrine, or
  11Cepinephrine , 18FDOPA , 18FDA
• DA Dopamine DOPA dihydroxyphenylalanine
• FDG fluorodeoxyglucose

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• FDG-PET may be good for localizing
  dedifferentiated and/or rapidly growing PHEO
  tumors. Nonspecific for PHEO and should never be
  used as an initial study
• 18FDOPA is a precursor of DA and has also been
  used in patients with PHEO. Normal adrenals do
  not show 18FDOPA uptake
• DA is a more specific substrate for the
  norepinephrine transporter compared with most
  other amines, including norepinephrine or DOPA.
  Excellent agent.

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FIG. 3. 18FFDG PET-reprojected image of a
22-yr-old female patient with a right PHEO.
Radionuclide uptake is evident over the right
adrenal (arrow). Studies with 123IMIBG and
Octreoscan were negative.
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18FDA PET-reprojected image of a 25-yr-old male
patient with a pelvic primary PHEO tumor (P) and
multiple metastatic lesions in the right humerus,
pelvis, abdomen, mediastinum, and thorax
(arrows). The renal calyces and the ureters are
prominent.

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A, 123IMIBG scan of a 63-yr-old patient with a
right adrenal PHEO. One focus of uptake is seen
(arrow). B, When the same patient was studied
with 18FDA PET, two foci of uptake were seen
(arrows)
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• 18FDA PET compared to MIBG
• Lower total cumulative radiation dose than
  131IMIBG
• Immediately exam

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Somatostatin receptor scintigraphy

• Types 1, 2, and 5 somatostatin receptors are
  abundantly expressed in different neuroendocrine
  tumors, whereas type 4 shows variable expression,
  and type 3 shows low expression in these tumors
• Up to 73 of PHEO cells express somatostatin
  receptors (predominantly types 2 and 4)

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• Octreotide is an eight-amino acid-long peptidic
  analog of somatostatin that is metabolically
  stable and has highest affinity for type 2
  somatostatin receptors, high affinity for type 5
  receptors, moderate affinity for type 3
  receptors, and no affinity for types 1 and 4
  receptors of somatostatin
• 111Indiaminetriaminepentacetate (DTPA), with a
  half-life of 2.8 d and -ray emissions of 173 and
  247 keV, is usually used for labeling octreotide.

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• Octreotide is predominantly (85) cleared by the
  kidneys within 24 h
• Sites of physiological uptake include mammary
  glands, liver, spleen, kidneys, bowel gall
  bladder, pituitary, thyroid, and salivary glands
  .Infections, inflammation, and recent surgery
  cause false positive results

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• Malignant/metastatic PHEO are better detected
  with Octreoscan compared with 123IMIBG (finding
  87 vs. 57 of lesions) , because MIBG as well as
  18FDA are sometimes negative in patients with
  malignant PHEO

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Widespread metastatic disease with lesions in the
chest, abdomen, right acetabulum, and right thigh
(arrows) seen on an Octreoscan of a 47-yr-old
patient with recurrent PHEO. Uptake of octreotide
in the right kidney is prominent (asterisk). In
this patient, 123IMIBG studies did not show
definite foci of uptake.
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Proposed imaging algorithm

• (1) Plasma metanephrine and normetanephrine
  (false positive results, such as
  phenoxybenzamine, tricyclic antidepressants, and
  ß-adrenoreceptor blockers ), clonidine test
• (2) Anatomical imaging methods (either CT or MRI)
  
• (3) Ruled out or confirmed with functional
  imaging (even if CT and MRI are negative, but
  PHEO is biochemically proven )

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• (4) The functional imaging test of choice is
  123IMIBG, or, if this is not available, then
  131IMIBG should be performed
• (5) If the MIBG scan is negative, PET studies
  should be performed with specific ligands,
  preferably 18FDA or 18FDOPA
• (6)Scintigraphy with nonspecific ligands, such
  as somatostatin receptor scintigraphy with
  Octreoscan or FDG PET for unusual type of PHEO or
  malignant PHEO

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• Thank You