Transcript Pheocromocytoma: An Update in Genetic Profiling, Diagnosis

Pheocromocytoma:
An Update in Genetic
Profiling, Diagnosis, Treatment
Roula BOU KHALIL
Endocrinology Division SGHUMC
Assistant Professor, Balamand University
OUTLINE
 Overview
 Epidemiology
 Updates in Genetics
 Diagnosis (biochemical and imaging)
 Treatment
OVERVIEW
OVERVIEW
 Pheochromocytoma 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
 80 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
EPIDEMIOLOGY
 Prevalence of PPGL is not precisely known
 Annual 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
 Equally in men and women
 Mean age at diagnosis 4th – 5th 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
 At 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
CLINICAL IMPORTANCE OF DIAGNOSIS
 Cardiovascular 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 tissue
 Mutations in the gene encoding SDH subunit B (SDHB) can lead to
metastatic disease in 40% or more
When to suspect pheochromocytoma?
 Hyperadrenergic spells
 Resistant hypertension
 A familial syndrome that predisposes to catecholamine-secreting
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tumors (eg, MEN2, NF1, VHL)
A family history of PPGL
An incidentally discovered adrenal mass
Hypertension and new onset or atypical diabetes mellitus
Pressor response during anesthesia, surgery, or angiography
Onset of hypertension at a young age (eg, <20 years)
Idiopathic dilated cardiomyopathy
A history of gastric stromal tumor or pulmonary chondromas
(Carney triad)
GENETICS
 Neurofibromatosis 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
NEUROFIBROMATOSIS 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
VON 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
 PHEO 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)
MULTIPLE 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 PHEOs
 PHEO 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)
 Codon 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
PARAGANGLIOMAS (PGLs)
SYMPATHETIC 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
PARASYMPATHETIC PARAGANGLIOMAS
 Usually found in the head and neck region
 usually biochemically silent, and malignancy is seen in <10%
of the cases
 most frequent PGLs in the neck are carotid body tumors
 most common below the neck are abdominal periaortic–
pericaval tumors
 most frequent symptoms for the patients with head and neck
tumors were palpable neck mass (55%) and cranial nerve
palsies (16%), rarely hyperfunctioning
 PGLs below the neck are more commonly hyperfunctioning
 Retroperitoneal PGLs are more likely to be malignant with
distant metastases or local invasion
SUCCINATE DEHYDROGENASE
 The 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
tumors
 Disease-causing mutations in three genes (SDHB, SDHD, and
SDHC)
PGL–SDHD
 Autosomal-dominant syndrome
 Familial 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 tumors
 Maternal imprinting of SDHD, resulting in only paternal transmission of SDHD
associated disease
 PHEOs may be unilateral or bilateral and the mean age of diagnosis is 43 years
PGL–SDHB
 Autosomal-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 phenotype
 Malignant PHEOs are reported in 35-40 % in these patients
 Increased risk for renal cell carcinoma and papillary thyroid cancer
PGL–SDHC
 Mutations 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
GENETIC TESTING
 Germline 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 mutations
 Familial PPGLs inherited as autosomal-dominant  (50%)
chance of passing on the mutation to each child
 Family history can be found; however, SDHD and SDHB
mutations have age related penetrance reaching 100% by age 70
years
 Sudden death should also be recorded
GENETIC TESTING
 Younger 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)
Suggested diagram for genetic testing in pheochromocytomas and
functional paragangliomas after an extensive clinical evaluation of the patients
CLINICAL PRESENTATION
 TYPICAL SYMPTOMS
 Sudden 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 daily
 Other symptoms may include anxiety (50%), a sense of dread, tremor,
or paresthesias
 Cardiovascular 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
HYPERTENSION
 Hypertension 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
DIAGNOSIS
BIOCHEMICAL DIAGNOSIS
 Plasma free or urinary fractionated metanephrines as initial testing
 Despite the convenience of a spot urine sample, there is no
evidence to suggest that this should replace the standardized 24hour urine collection method
 When measuring the 24-hour urinary excretion of fractionated
metanephrines, urinary creatinine should be measured to verify
completeness of the urine collection
 Use liquid chromatography with mass spectrometric or
electrochemical detection methods rather than other laboratory
methods
 For measurements of plasma metanephrines, draw blood with the patient in the supine
position
 Higher 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 sampling
 Solitary increases in either normetanephrine or metanephrine elevated 3-fold or more
above upper cutoffs are also rare as false positives
 Elevations 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)
 High 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
IMAGING STUDIES
 Imaging 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
 MRI 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
FDG PET
 18F-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
Perioperative Medical
Management
 All patients with a hormonally functional PPGL should undergo
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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 blockers
Methyl-paratyrosine (metyrosine) inhibits catecholamine synthesis
and may be used in combination with adrenergic receptor
blockers for a short period before surgery
 Phenoxybenzamine 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
 Retrospective studies report that –adrenergic receptor blockers should
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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 reasonable
Note that complete prevention of intraoperative hypertension and
tachycardia cannot be achieved by any doses and combinations of
antihypertensive and other drugs
Treatment options for hypertensive crises include intravenous sodium
nitroprusside, phentolamine, or nicardipine
 Laparoscopic adrenalectomy
 Open 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.
 Major potential postoperative complications are
hypertension, hypotension, and rebound hypoglycemia
 Blood 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