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Roula  BOU KHALIL Endocrinology Division SGHUMC Roula  BOU KHALIL Endocrinology Division SGHUMC

Roula BOU KHALIL Endocrinology Division SGHUMC - PowerPoint Presentation

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Roula BOU KHALIL Endocrinology Division SGHUMC - PPT Presentation

Assistant Professor Balamand University Pheocromocytoma An Update in Genetic Profiling Diagnosis Treatment OUTLINE Overview Epidemiology Updates in Genetics Diagnosis biochemical and imaging ID: 913690

tumors patients mutations disease patients tumors disease mutations ppgl ppgls tumor hypertension neck vhl age gene sympathetic pheos sdhb

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Slide1

Roula BOU KHALILEndocrinology Division SGHUMCAssistant Professor, Balamand University

Pheocromocytoma

:

An

Update in Genetic

Profiling, Diagnosis, Treatment

Slide2

OUTLINEOverview EpidemiologyUpdates in GeneticsDiagnosis (biochemical and imaging)

Treatment

Slide3

OVERVIEW

Slide4

OVERVIEWPheochromocytoma 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

Slide5

Slide6

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

Slide7

EPIDEMIOLOGY

Slide8

Prevalence 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

Slide9

Equally 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

Slide10

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

Slide11

CLINICAL 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

Slide12

When 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)

Slide13

GENETICS

Slide14

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

Slide15

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

Slide16

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

Slide17

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)

Slide18

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 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)

Slide19

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

Slide20

PARAGANGLIOMAS (PGLs)

Slide21

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

Slide22

PARASYMPATHETIC 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

Slide23

most 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

Slide24

SUCCINATE 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)

Slide25

PGL–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

Slide26

PGL–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

Slide27

PGL–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

Slide28

GENETIC 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

Slide29

GENETIC 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)

Slide30

Suggested diagram for genetic testing in

pheochromocytomas

and

functional

paragangliomas

after an extensive clinical evaluation of the patients

Slide31

Slide32

CLINICAL PRESENTATION

Slide33

Slide34

TYPICAL 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

Slide35

HYPERTENSIONHypertension 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

Slide36

DIAGNOSIS

Slide37

BIOCHEMICAL 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

Slide38

For 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)

Slide39

Slide40

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

Slide41

Slide42

IMAGING 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

Slide43

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

Slide44

FDG 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

Slide45

Perioperative Medical Management

Slide46

All 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

Slide47

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

Slide48

Retrospective 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

Slide49

Laparoscopic 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.

Slide50

Major 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