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Grand round 99/3/26 problem  LIST Grand round 99/3/26 problem  LIST

Grand round 99/3/26 problem LIST - PowerPoint Presentation

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Grand round 99/3/26 problem LIST - PPT Presentation

32yo woman with Hx of prolactinoma Amenorrehea Recurrent hypoglycemic attacks Hypercalcemia and elevated PTH and low BMD Fatigue and weakness Adrenal mass Empty sella agenda Empty sella and Apoplexy in MEN1 ID: 918954

patients men1 treatment adrenal men1 patients adrenal treatment tumors pituitary surgery empty sella parathyroidectomy parathyroid mass suggested management apoplexy

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Slide1

Grand round

99/3/26

Slide2

problem LIST

32y/o woman with:

Hx of prolactinoma

Amenorrehea

Recurrent hypoglycemic

attacks

Hypercalcemia and elevated PTH and low BMD

Fatigue and weakness

Adrenal mass

Empty sella

Slide3

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Adrenal mass

Hyperparathyroidism

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

Screening

in individuals at high risk of developing

MEN1

Slide4

Slide5

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Hyperparathyroidism

Adrenal mass

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

S

creening

in individuals at high risk of developing

MEN1

Slide6

J Clin Endocrinol Metab, February 2002, 87(2):457–465

Data

on pituitary disease were compared

with those

from 110 non-MEN1 patients with pituitary adenomas

,

In our MEN1 series,

pituitary disease

occurred in

136 of 324

(42

%),

Mean age of onset of pituitary

tumors was

38.0

±

15.3 yr

.

37

of the

136 patients

with pituitary disease had concomitantly

diagnosis of

pituitary adenoma and another endocrine lesion

Slide7

MEN1 pituitary adenomas were significantly

more frequent in women than in men

(50%

vs.

31%,

P

<0.001).

Mean

age of patients with

prolactinomas was

significantly younger

than that of other types of pituitary

adenomas (35.114.8

vs.

43.814.4 yr,

P<

0.001

). Among the 136 pituitary lesions, 19 were microadenomas (14%), and 116 were macroadenomas (85%),

J Clin Endocrinol Metab, February 2002, 87(2):457–465

Slide8

The median follow-up

period

was 11.4 yr.

Normalization of the pituitary hypersecretion occurred, on treatment, in 49 patients (42%),

Hypopituitarism developed after treatment in 8 patients (7%).

Among the 85 prolactinomas, plasma PRL levels were normalized in only 37 patients (44%).

J Clin Endocrinol Metab, February 2002, 87(2):457–465

Slide9

Comparison with non-MEN1 pituitary adenomas

J Clin Endocrinol Metab, February 2002, 87(2):457–465

Slide10

Outcome of pituitary adenomas

Indeed

, we show that prolactinomas in MEN1

are characterized

by a larger size but also by a worse

response to

therapy.

Thus

, our data suggest that prolactinomas

in MEN1

may be more aggressive than those occurring in

non- MEN1

patients.

Slide11

risk factors of Pituitary apoplexy

A

cute

increase in hypophyseal blood

flow

: hypertension or microvascular

degeneration, as seen in

diabetes,

large size of tumor

R

educed

blood flow to the pituitary

tumor

: transient

increase in

intracranial pressure

or systemic procedures such as cardiac

surgery

Hormonal stimulation

of the pituitary gland and

tumor

:

pregnancy,

the stress

response, or

exogenous

estrogen

therapy , active and withdrawal of bromocriptine therapyAn anticoagulated state :anticoagulation through drugs or immunodeficiency thrombocytopenia

Springer Science+Business Media New York 2014

Slide12

CNS & Neurological Disorders - Drug Targets

, 2012,

11

, 1012-1014

Pituitary tumor apoplexy appeared more frequently in

macroprolactinomas

than in microprolactinomas and also within a year and a half since the beginning of treatment with DA

Slide13

We were also concluded that apoplexy appears asymptomatic

and because

of that and because of more frequently appearing

in macroprolactinomas,

there are recommendations for performing MRI

imaging

of sellar region more

often

in patients

with macroprolactinomas

than in patients with microprolactinomas who are treated with DA.

CNS & Neurological Disorders - Drug Targets

, 2012,

11

, 1012-1014

Slide14

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Hyperparathyroidism

Adrenal mass

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

Screening

in individuals at high risk of developing

MEN1

Slide15

Adrenal Tumors in men1

The

incidence :

20% to 55

%

Most

affected patients are asymptomatic, as the majority of tumors

, are

NF.

I

ndeed

, fewer than 10% of patients

,have

biochemical evidence of hormonal hypersecretion,

P

rimary

hyperaldosteronism and

ACTH-independent Cushing syndrome

are the most commonly

encountered.

T

he

occurrence of

pheochromocytoma,

is rare

.

Slide16

Methods:

Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas.

European Journal of Endocrinology (

2012)166

269–279

Slide17

European Journal of Endocrinology (2012)166 269–279

Slide18

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012)

166

ACTH-independent Cushing’s syndrome was found in 5.5% of patients with adrenal tumours.

Interestingly

, Cushing’s syndrome was due to a unilateral disease in

3 of

the four of

our cases with a frank asymmetry in size in favour of the adenoma allowing unilateral adrenalectomy.

Slide19

No genotype–phenotype correlation was evident for the occurrence of adrenal lesions, adrenal tumours and occurrence of endocrine hypersecretion or ACC.

Specifically

, there was no statistical difference for the occurrence of adrenal lesions between patients with germline mutations in exons 2 and 10 and those with mutations in other exons in the menin gene.

European Journal of Endocrinology (2012)166 269–279

Slide20

Records of follow-up were available for 53 patients

with adrenal

lesions for a mean duration of

7.4 ± 0.8

(3–72

) months

.

During

follow-up, 13 of the 53

patients (24.5

%) showed a significant increase in size of

the adrenal

lesion and two (4%) developed a

contralateral lesion

of more than 10 mm in size.

Ten

ACCs

occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal

tumours in

two of the eight affected patients.

European Journal of Endocrinology (2012)166 269–279

Slide21

Men1 -associated adrenal mass COMPARED TO INCIDENTALOMA

E

ndocrine

hypersecretion

among MEN1 patients with adrenal tumours was 15.3% (11/72) and was significantly increased compared with the 6.9% (10/144) prevalence found in adrenal incidentalomas .

The

frequency of

primary hyperaldosteronism

and overt

ACTH-independent

Cushing’s syndrome

was significantly increased in MEN1 patients with adrenal tumours compared with patients with sporadic incidentalomas (

P<0.05

).

On

the contrary, the prevalence of pheochromocytoma was lower in MEN1 patients (

P<0.05

).

European Journal of Endocrinology (2012)166 269–279

Slide22

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Adrenal mass

Hyperparathyroidism

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

Screening

in individuals at high risk of developing

MEN1

Slide23

pancreatic NET

The aim of treatment for individuals with

symptomatic

insulinoma

is

to achieve

cure, if possible, by surgery

.

Surgical

treatment, which ranges from

enucleation

of

a single

tumor to

distal pancreatectomy

or

partial

pancreatectomy

, or

excision of all the macroscopic

pancreatic tumors

with enucleation of nodules in the remaining

pancreas has

been curative

in many patients.

Treatment

of nonresectable tumor mass includes somatostatin

analogs,

targeted radionuclide therapy, locoregional treatments, and chemotherapy

Slide24

surgical resection for nonfunctioning

pancreatic

NET

The role of surgery for nonfunctioning pancreatic tumors is controversial.

More than 1 cm in size

Less than 1 cm in size

,

for those that

have significant growth

, such as a doubling of tumor size,

over a

3- to 6-month interval and exceed 1

cm in

size

.

it

is

important to

consider that occult metastatic disease (

i.e.

tumors

not detected

by imaging investigations) may be present in

a substantial

proportion of these patients at the time of

initial presentation

, and that after surgery further tumors are likely to recur in remnant pancreatic tissue

Slide25

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Adrenal mass

Hyperparathyroidism

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

Screening

in individuals at high risk of developing

MEN1

Slide26

Management of adrenal mass

Biochemical investigation

should

be undertaken for those with

symptoms

or signs suggestive of functioning adrenal tumors, or for those with

tumors larger than 1 cm.

The incidence of ACC is reported to be approximately 1% in MEN1 patients but is higher (at approximately 13%) in MEN1 patients with adrenal tumors larger than 1 cm.

Thus, it is important that MEN1 patients with adrenal tumors are offered annual imaging

Slide27

N

onfunctioning

a

drenal tumors :

larger than 4 cm

in diameter

Atypical

or suspicious radiologic features

(e.g., increased Hounsfield units on an unenhanced CT scan) and

are

1 to 4 cm in

diameter

Show

significant measurable growth

over a 6-month

interval

The treatment of

functioning

(i.e., secreting) adrenal tumors in MEN1 patients is similar to that for tumors occurring in non-MEN1 patients

.

Surgery is recommended

Slide28

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Adrenal mass

Hyperparathyroidism

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

Screening

in individuals at high risk of developing

MEN1

Slide29

Parathyroid Tumors IN MEN1

PHPT

is the

most common feature

of

MEN1,occurs

in approximately 95% of all

patients,

and is the

first manifestation

in 75% to 90% of

patients.

The

degree of hypercalcemia is

usually mild

, and severe hypercalcemia or parathyroid carcinoma is rare

.

Slide30

MEN1-associated PHPT

compared TO

non-MEN1

PHPT

Early

age of

onset

An

equal sex distribution (male to female, 1:1 vs. 1:3,

respectively

)

The

synchronous or asynchronous involvement of all four parathyroid glands with

tumors

Greater

reduction in bone mineral

density

Slide31

SURGERY OR conservative

treatment

Surgical removal

of the abnormally overactive parathyroid glands in patients with MEN1 is the definitive treatment, but it is controversial whether to perform subtotal (3.5 glands) or total parathyroidectomy

(

extent

of surgery

)

and whether

surgery should be performed at an early or late stage of the

disease

(timing

of surgery

)

Currently, surgery is recommended for MEN1-associated PHPT in those with symptomatic disease

Slide32

SURGERY

Most centers will recommend

subtotal parathyroidectomy

(removal of 3–3.5 glands) or

total parathyroidectomy

with or without autotransplantation of cryopreserved parathyroid

tissue.

Concurrent

transcervical thymectomy

is also suggested at the time of neck surgery to remove parathyroid tumors that may be embedded in the thymus.

Minimally invasive selective parathyroidectomy, unilateral clearance, and less than subtotal parathyroidectomy (i.e., removal of <3–3.5 glands) are not recommended because all four parathyroid glands are usually affected with multiple adenomas or hyperplasia, although this histologic distinction may be difficult.

The aims of parathyroid surgery in MEN1 are to maintain normocalcemia for as long as possible and to avoid iatrogenic complications of surgery, including laryngeal nerve damage and permanent hypoparathyroidism

Slide33

Subtotal parathyroidectomy

or

total parathyroidectomy

Total parathyroidectomy with autotransplantation

:

B

oth

fresh and

cryopreserved parathyroid

tissue has been

used

V

itality

of cryopreserved

cells, decreases

with the time interval

from cryopreservation to autotransplantation

I

t

avoids the necessity for vitamin D medication for the

patient

T

he

transplanted parathyroid

tissue(in forearm) can be removed under local anesthesia, and reoperation of the neck under general anesthesia can be avoided

Slide34

Subtotal parathyroidectomy :

P

ersistent

or recurrent hypercalcemia within 10 to 12 yr after surgery in 40 to 60% of patients,

Subtotal

parathyroidectomy is suggested as the initial treatment of primary hyperparathyroidism in MEN1, but total parathyroidectomy with autotransplantation may also be considered for those with extensive disease either at first or at repeat surgery.

Subtotal parathyroidectomy

or

total parathyroidectomy

Slide35

conservative treatment

Management

of

hypoparathyroidism can

be challenging in some patients,

even with

the use of vitamin D and calcium replacement.

One recommendation

is that parathyroidectomy be

reserved for

symptomatic hypercalcemic

patients with

MEN1

Management

of asymptomatic MEN1 patients, including children and young adults who manifest only mild biochemical

features:

some centers advocate

early treatment

to minimize impacts on bone health, whereas others favor

conservative treatment

involving the regular assessment of patients for the onset of symptoms and/or associated complications.

Slide36

However, the timing of

surgery requires careful consideration, and factors

such as

surgical experience, availability of facilities for

long term

regular

serum calcium monitoring, accessibility

of calcitriol

(or vitamin D analogs), and patient

preference should

be taken into account

.

Cinacalcet

, has been used in MEN1 patients with PHPT in whom surgery is contraindicated because of comorbidities or where surgery has failed to cure the PHPT.

Slide37

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Adrenal mass

Hyperparathyroidism

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

S

creening

in individuals at high risk of developing

MEN1

Slide38

MEN1-associated pituitary tumors

Treatment of MEN1-associated

pituitary tumors

is similar to that for non-MEN1 pituitary tumors and consists of appropriate

medical

therapy

or

selective

transsphenoidal surgical

hypophysectomy, with

radiotherapy

reserved for residual unresectable tumor

tissue

Treatment

in MEN1 patients with hormonally secreting pituitary adenomas was significantly less effective in restoring the hypersecretion of hormones to normal

Surgery

will be required more frequently in the treatment of MEN1-associated than in non-MEN1 pituitary

adenomas

Slide39

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Hyperparathyroidism

Adrenal mass

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

S

creening

in individuals at high risk of developing

MEN1

Slide40

Who should be tested?

In

an index

case :

Meeting

the clinical criteria for

MEN1

Suspicious (

i

.

e

. multiple parathyroid adenomas before

the age

of 40

yr

,

multiple pancreatic NET at any age)Atypical for MEN1

(

i

.

e

. development of two nonclassical

MEN1-associated

tumors,

e.g.

parathyroid and adrenal tumor

)

A first-degree relative of family member with known MEN1:Asymptomatic first-degree relative of family member with known MEN1 mutation

Slide41

MEN1 mutational analysis in a

symptomatic family

member (

i.e.

an individual already showing

a clinical

manifestation of MEN1) from a family with

a known

MEN1

mutation has been challenged as being

unnecessary to

establish the diagnosis of MEN1.

However ,two

studies have reported that 5–10% of MEN1

kindreds have

the occurrence of phenocopies, which may

confound the

diagnosis ,

and

therefore we suggest that MEN1

family members

with one MEN1-associated tumor

should be

offered MEN1 mutation analysis.

Slide42

Multiple endocrine neoplasia type 4 (MEN4)

Approximately

5–10%

of patients with MEN1 do not have

mutations of

the MEN1 gene

,

and these patients may have mutations involving

other genes.

One of these genes is the

CDNK1B

,

which in man is located on

chromosome

12p13

and

encodes the

196 amino

acid cyclin-dependent kinase inhibitor (CK1)

p27kip1(

p27 protein

)

approximately 3% of these patients with MEN1-associated tumors, such as parathyroid adenomas, pituitary adenomas and pancreatic NETs in association with gonadal, adrenal, renal and thyroid tumors have CDNK1B mutations.

Slide43

When should testing be undertaken?

As

early as

possible

(

e.g.

before 5 yr of age for

asymptomatic individuals)

Slide44

agenda

Empty sella and Apoplexy in MEN1

Adrenal involvement in MEN1

Treatment management in this patient

Insulinoma

Hyperparathyroidism

Adrenal mass

Prolactinoma and empty sella

Suggested

approach for

MEN1

mutational analysis

in a clinical

setting

S

creening

in individuals at high risk of developing

MEN1

Slide45

Suggested Screening Guidelines for Individuals at Risk of MEN1

Slide46