Assistant Professor Balamand University Pheocromocytoma An Update in Genetic Profiling Diagnosis Treatment OUTLINE Overview Epidemiology Updates in Genetics Diagnosis biochemical and imaging ID: 913690
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Slide1
Roula BOU KHALILEndocrinology Division SGHUMCAssistant Professor, Balamand University
Pheocromocytoma
:
An
Update in Genetic
Profiling, Diagnosis, Treatment
Slide2OUTLINEOverview EpidemiologyUpdates in GeneticsDiagnosis (biochemical and imaging)
Treatment
Slide3OVERVIEW
Slide4OVERVIEWPheochromocytoma is a tumor arising from adrenomedullary
chromaffin
cells that commonly produces
one
or more
catecholamines
: epinephrine,
norepinephrine, and
dopamine
Rarely, these tumors are biochemically silent.
Paraganglioma
is a tumor derived from
extra-adrenal
chromaffin
cells
sympathetic
paravertebral ganglia
of thorax, abdomen, and
pelvis
parasympathetic
ganglia located along
the glossopharyngeal
and vagal nerves in the neck and at
the base
of the
skull, these
do not produce
catecholamines
Slide5Slide680 to 85% of chromaffin-cell tumors are pheochromocytomas,15 to20%are paragangliomas
During
the last few years, a considerable amount of new data concerning the genetics of
PHEO/PGL or
PPGL
25% of cases develop secondary to
germline
mutations
‘ Tip of
an iceberg’
because beyond a single tumor there is potentially a broader clinical picture
Slide7EPIDEMIOLOGY
Slide8Prevalence of PPGL is not precisely knownAnnual incidence of pheochromocytoma
is approximately
0.8 per 100,000 person years
Prevalence
of PPGL in patients with
hypertension in
general outpatient clinics varies between 0.2 and 0.6
%
Autopsy studies
demonstrate undiagnosed tumors in
0.05–0.1%In children with hypertension, prevalence of PPGL is approximately 1.7%Nearly 5% of patients with incidentally discovered adrenal masses on anatomical imaging prove to have a pheochromocytoma
Slide9Equally in men and womenMean age at diagnosis 4
th
– 5
th
decades
large
number of patients have non classic symptoms such as abdominal pain, vomiting, dyspnea, heart failure, hypotension, or sudden death, suggesting that the majority of PHEOs are not diagnosed during
life
Most
PHEOs are
sporadic with prevalence of malignancy 9%About 10% of patients with PHEOs present with metastatic disease at the time of their initial work-up
Slide10At least one-third of all patients with PPGLs have disease-causing germline mutations (inherited mutations present in all cells of the
body)
The
prevalence
of PPGL
in individuals carrying a
germline
mutation
in PPGL
susceptibility genes may be around 50
%.Patients with hereditary PPGLs typically present with multifocal disease and at a younger age than those with sporadic neoplasms
Slide11CLINICAL IMPORTANCE OF DIAGNOSISCardiovascular morbidity and mortality due to excess catecholamines if left untreated
PPGL may enlarge
mass effect
For familial
disease, detection of a tumor in the
proband
may result
in earlier diagnosis and treatment in other
family members
Some PPGLs have malignant potential, defined as the presence of metastases in nonchromaffin tissueMutations in the gene encoding SDH subunit B (SDHB) can lead to metastatic disease in 40% or more
Slide12When to suspect pheochromocytoma?Hyperadrenergic spells Resistant hypertension
A
familial syndrome that predisposes to catecholamine-secreting tumors (
eg
, MEN2, NF1, VHL
)
A family
history
of
PPGL
An incidentally discovered adrenal massHypertension and new onset or atypical diabetes mellitusPressor response during anesthesia, surgery, or angiographyOnset of hypertension at a young age (eg, <20 years)Idiopathic dilated cardiomyopathyA history of gastric stromal tumor or pulmonary chondromas
(Carney triad)
Slide13GENETICS
Slide14Neurofibromatosis 1 (NF1)Von Hippel–Lindau
(
VHL)
Multiple endocrine
neoplasia
type 2
(
MEN2A & MEN 2B)
PPGL
syndromes based
on mutations of the genes for succinate dehydrogenase subunit D (SDHD), B (SDHB), and C (SDHC)Others
Slide15NEUROFIBROMATOSIS 1 (NF1)
NF1 is caused by inactivating mutations
of
neurofibromin
, a tumor suppressor gene
which encodes
a
GTPase
-activating protein involved in the inhibition of
Ras
activity, which controls cellular growth and differentiation
chromosome
17q11.2
PHEOs are benign (90%) and single (84%),
followed by
bilateral (10%) and sympathetic PGLs (
6%), occur in adulthood
produce predominantly norepinephrine
(NE) and therefore present
with hypertension
and noradrenergic symptomatology
Slide16VON HIPPEL -LINDAU (VHL)
Autosomal-dominant disease with
an
incidence of
1
in3600births
PHEO develops in 20%of
patients with VHL, with a mean age at onset
in the
second decade of life, although such tumors
often occur even later
Mutations
of
the VHL gene (tumor suppressor gene) localized
to chromosome
3p25–26
Hemangioblastoma
in the retina, cerebellum
and spine; renal cell carcinoma (clear
cell type
); PHEO;
islet
tumors of the pancreas;
endolymphatic
sac
tumors; and
cysts
and
cystadenoma
in the kidney,
pancreas
, epididymis, and broad ligament
Slide17PHEO may present as the first or only manifestation of VHL (VHL type 2C) VHL carriers can present as apparently
sporadic PHEO
Sympathetic PGL have been described also (10%)
Approximately half
of PHEOs
are bilateral and most produce
NE (norepinephrine)
Slide18MULTIPLE ENDOCRINE NEOPLASIA 2 (MEN2)Autosomal-dominant syndrome caused by activating mutations in the RET proto-oncogene located on
chromosome
10q11.2
MEN2A is characterized
by medullary thyroid carcinoma (MTC
), hyperparathyroidism
, and
PHEO
MEN2B
is
characterized by MTC, marfanoid habitus, mucosal ganglioneuromas, and PHEOsPHEO occurs in approximately half of gene carriers and is almost always located within the adrenal glands, half of these are bilateral but asynchronous (up to 15 years apart)
Slide19Codon 634 (MEN2A) or 918 (MEN2B) RET protooncogene mutations Malignant
PHEOs
are uncommon <5% generally with large tumors
The
pattern
of catecholamine
production in MEN2 PHEO differs
from that
seen in other hereditary forms of PHEO.
Epinephrine (E) +++ early clinical phenotype
Slide20PARAGANGLIOMAS (PGLs)
Slide21SYMPATHETIC PARAGANGLIOMAS Derived from the sympathetic chain Located in the chest, abdomen, or
pelvis
Clinical picture due to either
the secretion
of
catecholamines
or the size of the tumors
The
frequency of malignancy is much higher
in sympathetic tumors with extraadrenal location
Slide22PARASYMPATHETIC PARAGANGLIOMASUsually found in the head and neck regionusually biochemically silent,
and malignancy
is seen
in <10
% of the
cases
most
frequent PGLs in the
neck are carotid
body
tumorsmost common below the neck are abdominal periaortic–pericaval tumors
Slide23most frequent symptoms for the patients with head and neck tumors were palpable neck mass (55%) and cranial nerve palsies (16%), rarely hyperfunctioningPGLs below the neck are more commonly hyperfunctioning
Retroperitoneal PGLs are more likely to be malignant with distant metastases or local invasion
Slide24SUCCINATE DEHYDROGENASEThe succinate dehydrogenase (SDH) is a mitochondrial enzyme complex with an important role in oxydative phosphorylation and intracellular
oxygene
sensing and
signaling
Evidence
that tumor genesis in
PGL syndromes
is linked to activation of
hypoxia-related pathways
Constant
signaling of hypoxia in the cell highly vascularized tumorsDisease-causing mutations in three genes (SDHB, SDHD, and SDHC)
Slide25PGL–SDHDAutosomal-dominant syndromeFamilial and isolated head and neck parasympathetic
PGLs and less frequently by
sympathetic PGLs
and
PHEOs
Mutations in SDHD
gene located on chromosome
11q21–23
generally
benign, multifocal tumorsMaternal imprinting of SDHD, resulting in only paternal transmission of SDHD associated diseasePHEOs may be unilateral or bilateral and the mean age of diagnosis is 43 years
Slide26PGL–SDHBAutosomal-dominant syndrome characterized by sympathetic extraadrenal PGLs and
malignant
disease
Inactivating mutations
in the tumor suppressor SDHB gene
located on
chromosome
1p35–36
No maternal imprinting
Very strong association with a malignant intra- or extraadrenal phenotypeMalignant PHEOs are reported in 35-40 % in these patientsIncreased risk for renal cell carcinoma and papillary thyroid cancer
Slide27PGL–SDHCMutations in SDHC gene located on chromosome 1q21 Autosomal dominant
No maternal imprinting
Benign
and seldom multifocal head
and neck
parasympathetic
PGL
In the last few years, four new genes (SDHA, SDHAF2, MAX, and TMEM127 ) have been found to be associated with predisposition to these
tumours
Slide28GENETIC TESTINGGermline mutations are responsible for about 25% of cases instead of 10% thought to be hereditary
previously
7.5–27
% of
tumors without
an obvious syndrome or family history
result from
otherwise unsuspected
germline
mutationsFamilial PPGLs inherited as autosomal-dominant (50%) chance of passing on the mutation to each childFamily history can be found; however, SDHD and SDHB mutations have age related penetrance reaching 100% by age 70 yearsSudden death should also be recorded
Slide29GENETIC TESTINGYounger age as hereditary PPGL occur at younger age than sporadic tumors
Genetic
testing is more
necessary in
young adults, especially for VHL
disease and SDHB
Extraadrenal
,
multifocal
disease SDHB/SDHD gene mutations Endocrine Society guidelines (2015) recommend that all patients with PPGLs should be engaged in shared decision making for genetic testing (but not necessarily done in each patient)
Slide30Suggested diagram for genetic testing in
pheochromocytomas
and
functional
paragangliomas
after an extensive clinical evaluation of the patients
Slide31Slide32CLINICAL PRESENTATION
Slide33Slide34TYPICAL SYMPTOMSSudden rise of BP with concurrent episodes of headache (80%), diaphoresis (70%),
and palpitations
(60
%) pallor
Episodes
usually last
minutes or hours
Paroxysms
may not recur
for months
or may recur many times dailyOther symptoms may include anxiety (50%), a sense of dread, tremor, or paresthesiasCardiovascular symptoms (arrythmia, HF, cardiomyopathy)Neurologic manifestations (stroke, confusion, seizures) About 8% of patients may
be completely
asymptomatic, usually those with
familial forms
of the disease or with large, cystic tumors
Slide35HYPERTENSIONHypertension is paroxysmal in 48% of patients, persistent in 29%, and 13% have normal
BP
NE-secreting tumors
are usually associated with sustained hypertension.
Tumors
that secrete large amounts of E
together with
NE are associated with episodic hypertension.
Pure
E-producing tumors can produce
hypotension rather than hypertension
Slide36DIAGNOSIS
Slide37BIOCHEMICAL DIAGNOSISPlasma free or urinary fractionated metanephrines as initial testingDespite the convenience of a spot urine
sample, there
is no evidence to suggest that this should replace
the standardized
24-hour urine collection
method
When measuring the 24-hour urinary excretion of
fractionated
metanephrines
, urinary
creatinine should be measured to verify completeness of the urine collectionUse liquid chromatography with mass spectrometric or electrochemical detection methods rather than other laboratory methods
Slide38For measurements of plasma metanephrines, draw blood with the patient in the supine positionHigher
concentrations of plasma
metanephrines
in upright positions
of blood sampling than in supine
positions
Patients
should be
fully recumbent
for at least 30 minutes before
samplingSolitary increases in either normetanephrine or metanephrine elevated 3-fold or more above upper cutoffs are also rare as false positivesElevations of both normetanephrine and metanephrine
are rare as
false-positives
For
plasma free
metanephrines
, dietary
considerations are
only relevant when measurements include the
dopamine metabolite 3-methoxytyramine (
overbight
fast)
Slide39Slide40High suspicion of PPGL plasma free metanephrines
Low suspicion of PPGL
24-hour urinary fractionated
catecholamines
and
metanephrines
Chromogranin
A (CGA) tumor marker, for follow up mainly in malignant disease, elevated in NE tumors
Slide41Slide42IMAGING STUDIESImaging studies to locate PPGLs should be initiated once there is clear biochemical evidence of a
PPGL
CT
rather than MRI as the
first-choice imaging
modality
high HU density on
noncontrast
CT, marked enhancement with IV contrast on CT with delayed contrast washout [<50% at 10
mins
], cystic & hemorrhagic changes, bilaterally, or larger size [>4 cm])A high signal intensity (bright) T2-weighted MRI image may be of value for the detection of PPGLs; however, a recent study showed that in pheochromocytomas this finding
is relatively
uncommon
Slide43MRI recommended in patients with metastatic PPGLs, for detection of skull base and neck paragangliomas, in patients with an allergy to CT contrast,
and in
patients in whom radiation exposure should be
limited (children
, pregnant women, patients
with known
germline
mutations
, and those with recent excessive radiation exposure
)123I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with metastatic PPGLs,in some patients with an increased risk for metastatic disease due to large size of the primary tumor, or recurrent disease
Slide44FDG PET18F-FDG PET/CT is the preferred imaging modality over 123I-MIBG scintigraphy
in
patients with known metastatic PPGLs
Sensitivity
of 18F-FDG PET
was shown
to be between 74 and 100%, with the highest
performance for
metastatic, particularly
SDHB-related PPGLs Other imaging — 111-In-pentetreotide scintigraphy (Octreoscan), DOPA PET
Slide45Perioperative Medical Management
Slide46All patients with a hormonally functional PPGL should undergo preoperative blockade to prevent perioperative cardiovascular complications
Adrenergic
receptor blockers as
the first choice
Calcium channel blockers are the most often
used add-on
drug class to further improve blood pressure
control
Preoperative
coadministration
of -adrenergic receptor blockers is indicated to control tachycardia only after administration of -adrenergic receptor blockersMethyl-paratyrosine (metyrosine) inhibits catecholamine synthesis and may be used in combination with adrenergic receptor blockers for a short period before surgery
Slide47Phenoxybenzamine is the preferred drug for preoperative preparation to control blood pressure and arrhythmia in most centers in the United States. It is an irreversible, long-acting, nonspecific alpha-adrenergic blocking agent, 20 and 100 mg
daily,
orthostasis
, nasal stuffiness and fatigue
With their more favorable side-effect profiles,
selective alpha1-adrenergic blocking agents
(
eg
,
prazosin
, terazosin, or doxazosin) are utilized in many centers or are preferred
Slide48Retrospective studies report that –adrenergic receptor blockers should be started at least 7 days preoperatively (better 10 – 14 days)high-sodium diet a few days after the start
of-adrenergic receptor
blockade
Continuous administration of
saline (1–2
L) is also helpful if started the evening
before surgery
Optimal
target blood
pressure? A target blood
pressure of less than 130/80mmHgwhile seated and greater than 90 mm Hg systolic while standing seems reasonableNote that complete prevention of intraoperative hypertension and tachycardia cannot be achieved by any doses and combinations of antihypertensive and other drugsTreatment options for hypertensive crises include intravenous sodium
nitroprusside
,
phentolamine
, or
nicardipine
Slide49Laparoscopic adrenalectomyOpen adrenalectomy (large tumors > 8 cm, malignant disease)
Partial
adrenalectomy
with cortical sparing in familial
pheochromocytoma
(High
incidence of bilateral
disease) to
prevent permanent glucocorticoid deficiency.
Slide50Major potential postoperative complications are hypertension, hypotension, and rebound hypoglycemiaBlood
pressure, heart
rate and plasma
glucose levels should be closely monitored
for 24–48 hours
Measure plasma
or urine levels
of
metanephrines
on follow-up to diagnose persistent disease (2-4 weeks after surgery)Lifelong annual biochemical testing to assess for recurrent or metastatic disease
Slide51