Download MULTIPLE ENDOCRINE NEOPLASIA (MEN)

MULTIPLE ENDOCRINE
NEOPLASIA (MEN)
PATHOPHYSIOLOGY
CHAPTER 10
Presented by
BEVERLY WILLIAMSCLEAVES,M.D.
CHIEF of ENDOCRINOLOGY
REGIONAL MEDICAL CENTER &
MEDPLEX ENDOCRINE CLINICS
MEN
DEFINITION:
A group of disorders characterized by functioning
tumors in more than one endocrine gland, an
autosomal dominant inheritance pattern and, for
some, the ability of affected cells to exhibit amine
uptake and decarboxylation(APUD).
MEN can be diagnosed if a patient has at least 2 of
the characteristic organs involved or if there is one
organ involved in the face of a family hx of MEN.
Table 3
1903 Erheim – Patient with acromegaly and four enlarged parathyroid
glands.
1927 Cushing and Davidoff – Patient with acromegaly, two enlarged
parathyroid adenomas and an islet cell tumor.
1939 Russier and Davidoff – Several members of the same family with
Multiple Endocrine Tumors.
1953
Underdahl et al. – Described eight patients with multiple adenomas
involving at least two of the three glands: pituitary, parathyroid, and
pancreas.
1954
Wermer – Coined the term adenomatosis of endocrine glands and
supported the idea of an autosomal dominant gene.
1961 Sipple – Autopsy findings in a patient with bilateral
pheochromocytomas, bilateral carcinoma of the thyroid and enlargement of one
parathyroid gland.
1968
Garlin et al – Multiple mucosal neuromas, pheochromocytoma and
medullary carcinoma of thyroid.
MEN 1
PITUITARY TUMORS
a)tend to be multicentric
b)prolactinomas are the most
common secretory tumors, usually
dx’ed by finding a prolactin of 100ug/L
or>, followed by
acromegaly(excessive growth
hormone &IGF-1) and Cushing’s
Disease(excessive ACTH & cortisol)
MEN 1
PERIODIC SCREENING in Suspected
Individuals
a)Check secretory hallmarks of secretory
pituitary tumors.
b)Pancreatic tumors:
1)Insulinomas---(measure insulin , blood
sugar and c peptide, fasting)
2)Zollinger-Ellison—secretin(gastrin increase
of >200pg in 15 min)-most sensitive; calcium
gluconate infusion->400pg rise of gastrin
MEN 1
GENETIC CONSIDERATIONS:
a)transmitted as an autosomal dominant
trait, located on chromosome 11q13,
which encodes a tumor suppressor protein
called menin. It usually interacts with
a transcriptional factor, Jun D.
b)affected individuals usually harbor a
germline mutation in MEN 1 but also
acquire a “second hit” in the normal
gene. Gene mutations are found in about 90%.
CLINICAL FEATURES of 18 PATIENTS with
PROVEN PRIMARY HYPERPARATHYROIDISM
Clinical Features
Sex
Male
Female
Elevated Serum ca#
Low Serum phos.
Elevated alk.phos.
Elevated PTH
Nephrolithiasis
# of Pts.
9/18
9/18
18/18
18/18
10/18
18/18
6/18
% of Pts
50
50
100
100
56
100
33
CLINICAL FEATURES of PRIMARY
HYPERPARATHYROIDISM…cont.
Clinical Features
Pts.
# of Pts.
Subperiosteal bone resorption 2/18
Large bone cysts
1/18
Surgery
1-2.5 glands excised
5/18
3-3.5/4 glands excised
13/18
Hyperplasia
13/18
Adenoma
3/18
Undetermined
2/18
Recurrent Hyperpara
6/18
%of
11
6
27
72
72
16
11
33
CHARACTERISTICS of PITUITARY TUMORS
Characteristic
Sex
Male
Female
Main presenting sxs
Female
Amenorrhea and galactorrhea
Headache
Visual fields defect
Male
Impotence
Headache
No. %
3(38%)
5(62%)
5/5
1
1
3
2
CLINICAL FEATURES of PRIMARY
HYPERPARATHYROIDISM…cont.
Clinical Features
Pts.
# of Pts.
Subperiosteal bone resorption 2/18
Large bone cysts
1/18
Surgery
1-2.5 glands excised
5/18
3-3.5/4 glands excised
13/18
Hyperplasia
13/18
Adenoma
3/18
Undetermined
2/18
Recurrent Hyperpara
6/18
%of
11
6
27
72
72
16
11
33
PITUITARY TUMOR CHARACTERISTICS cont.
Characteristic
No.(%)
Increase in size of hands and feet and
acromegalic features
Enlarged sella
7/8(88%)
Elevated prolactin
7/8(88%)
Elevated growth hormone
1/8(12%)
Table 5. Clinical and Biochemical Features in 14
Patients with Islet Cell Tumors
Symptoms
Biochemical Findings
H ypoglycemia (Insulinoma)
No. of
patients
Paradoxically high serum
insulin
High gastrin level high
acidity, and peptic ulcers
2
Skin lesions (Glucagonoma
syndrome)
High fasting glucagon level
1
No symptoms but detected
during family study
(Glucagonoma disease)
High fasting glucagon level
2
Fever and cough, metastasis in
in the chest from islet cell tumor
(Islet cell tumor)
Hormones not determined
3
6*
Peptic ulcer disease
(Zollinger-Ellison syndrome)
*Two of these patient are awaiting surgery .
MEN 2A
1)MEDULLARY THYROID CARCINOMA
The most common manifestation which develops in
childhood, beginning as hyperplasia of the
calcitonin-producing cells. Tumors>1cm are
frequently associated with local and distant
metastases.
2)PHEOCHROMOCYTOMAS
These are found in approx. 50% of 2A’s,
half of them being bilateral. Epinephrine production usually>norepinephrine.
3)HYPERPARATHYROIDISM in 15-20% of 2A’s.
Peak incidence is in the third or fourth decade.
MEN 2B
GENETIC FACTS:
Mutations of the RET proto-oncogene have
been noted in 93-95% of patients(chrom 10).
Naturally occurring mutations occur in two
regions of the RET tyrosine kinase receptor, the putative cysteine-rich extracellular
domain(codon 609, 611, etc.) and in the
substrate recognition pocket at codon 918.
Table 7. – Expression of Multiple
Endocrine Neoplasia Type 2b
No. of
Patients
Medullary thyroid cancer
Pheochromocytoma
Neuromas
Bumpy lips
Marfanoid habitus
Intestinal abnormalities*
Thickened corneal nerves
Skeletal abnormalities†
Delayed puberty
No. of Patients
With Information
Available
18
8
18
18
17
12
9
14
6
18
18
18
18
18
16
13
16
12
*Intestinal ganglioneuromatosis, megacolon, severe diarrhea, constipation
†Pes cavus, kyphosis, scoliosis, lordosis, pectus excavatum, skipped femoral epiphysis.
CHARACTERISTIC FEATURES of NEUROMAS
1)Found mostly in the oral cavity(tongue,
lips, buccal mucosa). Also seen on eyelids,
conjunctivae, cornea and gastrointestinal
tract.
2)The oral lesions occur very early in life,
often within the first decade or even at
birth.
3)The lesions consist of hypertrophied
nerve fibers.
MEN 2B
Dx & TREATMENT:
1)Genetic screening for early identification
of those at risk is key, given the potentially devastating results of metastatic
medullary carcinoma and undiagnosed
pheochromocytoma.
2) Children with codon 883, 918 and 922
should have a total thyroidectomy and central
lymph node dissection(general consensus)
MEN 2B
CLINICAL FEATURES:
MTC develops earlier than in 2A
Metastatic disease has been described
prior to age one.
Death can occur in the second or third
decade.
Pheos occur in more than 50% of patients.
Mucosal neuromas and the marfanoid habitus
are the most distinctive features and are usually
seen in childhood.
Table 2
Utility of various imaging modalities
for the diagnosis of
pheochromocytoma
CT
MRI
MIBG
Sensitivity
97.9%
100%
77.5%
Specificity
69.8%
66.7%
100%
Positive predictive value
66.1%
80.0%
100%
Negative predictive value
95.7%
100%
87.7%
Reprinted with permission from the New England Journal of
Medicine [11]
MEN 2B
Periodic Biochemical Screening:
1)Pheo—catecholamines, metanephrines,
VMA
2)Medullary Carcinoma---if genetic screening in an adult is positive, to document
onset of disease, pentagastrin provocative
testing might be helpful. Calcium can also
be used to stimulate calcitonin. Thyroidectomy should soon follow def. pos. results.
MEN
CASE STUDY: L.I
65 y/o WM veteran with the following Hx:
1)Neurofibromatosis-dx’ed age 27
2)Left adrenalectomy—age 36
3)S/p Total Thyroidectomy –age 48
Medications included. calcium carbonate,
thyroid replacement and Vitamin D 3x/wk
MEN
CASE STUDY continued:
Questions:
1)What is his dx?
2)Would you continue to do periodic catecholamine screening?
3)What kind of conversation would you
have with his family members?
4)What would you expect to find on
genetic
testing?