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
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Slide1
Grand round
99/3/26
Slide2problem 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
Slide3agenda
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
Slide4Slide5agenda
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
Slide6J 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
Slide7MEN1 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
Slide8The 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
Slide9Comparison with non-MEN1 pituitary adenomas
J Clin Endocrinol Metab, February 2002, 87(2):457–465
Slide10Outcome 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.
Slide11risk 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
Slide12CNS & 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
Slide13We 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
Slide14agenda
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
Slide15Adrenal 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
.
Slide16Methods:
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
Slide17European Journal of Endocrinology (2012)166 269–279
Slide18EUROPEAN 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.
Slide19No 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
Slide20Records 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
Slide21Men1 -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
Slide22agenda
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
Slide23pancreatic 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
Slide24surgical 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
Slide25agenda
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
Slide26Management 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
Slide27N
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
Slide28agenda
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
Slide29Parathyroid 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
.
Slide30MEN1-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
Slide31SURGERY 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
Slide32SURGERY
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
Slide33Subtotal 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
Slide34Subtotal 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
Slide35conservative 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.
Slide36However, 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.
Slide37agenda
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
Slide38MEN1-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
Slide39agenda
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
Slide40Who 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
Slide41MEN1 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.
Slide42Multiple 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.
Slide43When should testing be undertaken?
As
early as
possible
(
e.g.
before 5 yr of age for
asymptomatic individuals)
Slide44agenda
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
Slide45Suggested Screening Guidelines for Individuals at Risk of MEN1