Multiple endocrine neoplasia (men) syndromes

1. BY /Marwa Mahmoud Khalifa
Hematology Resident

2. Background
Multiple endocrine neoplasia (MEN) syndromes consist
of 2 categories, MEN type 1 (MEN1) and MEN type 2
(MEN2). MEN2 has been subcategorized into MEN2-
A, MEN2-B, and medullary thyroid cancer (MTC)–
only.

4. MEN type 1
 The combination of parathyroid tumors, pancreatic
islet cell tumors, and anterior pituitary tumors is
characteristic of MEN1.
 usually inherited as an autosomal dominant disorder
 can also occur sporadically (without a family history)
 In 1954, Wermer was the first to describe the syndrome
as a distinct clinical entity.

7. Etiology
 The responsible gene for (MEN1) is located at 11q13 and
codes for the menin protein. Menin is involved with
regulation of transcription and genome stability. Loss
of heterozygosity for this region is associated with
MEN1, suggesting that the gene has tumor suppression
function.
 MEN1 is an autosomal dominant disorder, but sporadic
mutations also occur.

8. Pathophysiology and presentations
Parathyroid tumors
 Primary hyperparathyroidism, caused by hyperplasia of
parathyroid glands, is the most common manifestation of
multiple endocrine neoplasia type 1 (MEN1) and occurs in
approximately 90% of all patients.
 Clinical manifestations can include hypercalcemia,
nephrolithiasis, and bone abnormalities (osteitis fibrosa
cystica).
 Common symptoms associated with hypercalcemia include
polydipsia, polyuria, constipation, and generalized malaise.

9.  Pancreatic islet cell tumors (neuroendocrine tumors)
 the second most common manifestation of MEN1 30-80% of
patients.
 Islet cell tumors encompass gastrinomas, insulinomas,
glucagonomas ,vasoactive intestinal polypeptidomas
(VIPomas), and pancreatic polypeptidomas (PPomas).
 often multicentric and may undergo malignant
transformation. These tumors can produce peptides and
biogenic amines.
 However, nonfunctioning pancreatic endocrine tumors are
the most common enteropancreatic neuroendocrine tumor.
 important to diagnose, as malignant pancreatic
neuroendocrine tumors are the most frequent cause of
death in people with MEN1.

10. Gastrinomas
 the most common functional pancreatic
neuroendocrine tumors.
 often small, multicentric, and located in the
duodenum, thus diminishing the probability of
surgical cure.
 The features predictive of poor prognosis include
pancreatic location of lesions, metastases, ectopic
Cushing syndrome, and high gastrin level.
 The development of gastrinomas is preceded by
multifocal hyperplasia of the gastrin-producing cells.

11. Insulinomas
 can be multicentric and can metastasize either to
regional lymph nodes or to the liver.
 Unlike non-MEN1 insulinomas, usually occur in
patients younger than 40 years and many are
diagnosed in patients younger than 20 years.
 Patients often present with hypoglycemic symptoms
after a fast, low blood glucose with symptoms
improving after glucose intake hypoglycemic
symptoms (Whipple’s triad).

12. Glucagonomas
 occur rarely (3%) in patients with MEN1
 can present silently or with hyperglycemia.
 Few patients show the typical skin lesions, known as
necrolytic migratory erythema.
 Other presenting symptoms can be anemia,
stomatitis, and weight loss, but these are often absent.

13. A characteristic rash called
necrolytic migratory
erythema seen in the face,
lower abdomen, perineum,
and lower extremities.

14. VIPomas
 occur in less than 1% of MEN1 patients.
 Presenting symptoms can include watery diarrhea,
hypokalemia, achlorhydria (WDHA syndrome).
Tumors secreting pancreatic polypeptide (PPomas)
may not be associated with clinical manifestations and
may be nonsecretory.
Growth hormone–releasing hormone tumors
(GHRHomas) have been reported in patients with
MEN1 and most commonly arise in the lungs, followed
by the pancreas and small intestine

15. Pituitary tumors
 MEN1-associated pituitary tumors most commonly
secrete prolactin (60%), followed by tumors that
secrete growth hormone (25%).
 Less than 5% secrete corticotropin and others are
nonfunctional.
 Compared with non-MEN1 pituitary tumors, they
tend to be larger (macroadenomas) and more
aggressive, with a higher rate of infiltration of tumor
cells into normal pituitary tissue.
 MEN1-associated pituitary tumors are less responsive
to therapy. However, there is no distinct histological
difference between MEN1 and non-MEN1 pituitary
tumors.

16. Other tumors associated with MEN1
 Carcinoid tumors can occur in patients with MEN1 and
are located in the bronchi, gastrointestinal tract, pancreas,
and thymus..Carcinoids can actively secrete hormones such
as serotonin, somatostatin, corticotropin, and growth
hormone.
 Cutaneous expression of MEN1 is common.
Subcutaneous lipomas are found in one third of MEN1
patients,can also be retroperitoneal, visceral, or pleural.
The presence of facial angiofibromas and collagenomas
may allow presymptomatic diagnosis of MEN1 in relatives
of diagnosed patients.
 Adrenal tumors occur and usually are nonfunctional.
They are most often benign 20-40% of patients. Adrenal
cortical carcinomas are rare in MEN1 patients
 Thyroid adenomas occur in 5-30% of patients and have
no specific MEN1-reported clinical significance.
 Meningiomas and other central nervous system tumors
have been reported.

17. Laboratory Studies
Gastrinomas
 Screening should start by age 20 years.
 The diagnosis of gastrinoma is confirmed by a
basal serum gastrin level >1000 pg/ml off proton-
pump inhibitors.
 A basal gastrin levels >250 pg/ml is suggestive and
can be confirmed with a secretion stimulation test

18. Insulinomas
 A supervised 72-hour fast is used most often to confirm
this diagnosis.
 Screening should start by age 5 years.
Glucagonomas
 Elevated serum glucagon levels and hyperglycemia are
present
 Screening should start in children younger than 10 years.
Vasoactive intestinal polypeptidomas (VIPomas)
 Elevated serum levels of vasoactive intestinal polypeptide
are present.
 Screening should start in children younger than 10 years.

19. Pancreatic polypeptidomas (PPomas)
 Pancreatic polypeptide levels are elevated.
 Chromogranin A levels can be elevated in any pancreatic
neuroendocrine tumor.
 Screening should begin by age 10 years.
Carcinoid tumors
 Elevated levels of chromogranin A, calcitonin, corticotropin, or
urinary 5-hydroxyindoleacetic acid (5-HIAA) can occur.
 screening is dependent on radiological imaging as no
biochemical abnormality has been consistently observed.
Pituitary tumors
 Assess growth hormone levels (insulinlike growth factor-1 [IGF-
1]) and prolactin.
 Screening should begin by age 5 years.
Hyperparathyroidism
 Calcium is elevated with an inappropriately elevated parathyroid
hormone level.
 Screening should start by age 8 years.

20. Imaging Studies
Sagittal (left image) and
coronal (right image), T1-
weighted magnetic
resonance images of the
brain in a patient with
multiple endocrine
neoplasia syndrome type 1
(MEN1). These images
show a pituitary
macroadenoma

21. octreotide scan in a
patient with multiple
endocrine neoplasia
syndrome type 1 (MEN1).
These nuclear images
demonstrate abnormal
activity in the pituitary
macroadenoma (curved
arrow), parathyroid
adenoma (straight arrow),
and gastrinoma
metastases throughout
the abdomen
(arrowheads).

22. (CT) scan of the
pancreas in a patient
with multiple endocrine
neoplasia syndrome
type 1 (MEN1) and a
gastrinoma. This image
shows a pancreatic head
mass (large, white
arrow), as well as a low-
attenuating lesion in the
liver (small, black
arrowhead) that
indicates metastases

23. (CT) scan image with
oral and intravenous
contrast in a patient
with biochemical
evidence of
insulinoma. The 3-cm
contrast-enhancing
neoplasm (arrow) is
seen in the tail of the
pancreas (P) posterior
to the stomach (S)

24. Endoscopic
ultrasonogram in a
patient with an
insulinoma. The
hypoechoic neoplasm
(arrows) is seen in the
body of the pancreas
anterior to the splenic
vein (SV).

25. •99mTc MIBI) in a patient
with multiple endocrine
neoplasia syndrome type 1
(MEN1). These images
demonstrate persistent
abnormal activity of the
inferior right parathyroid
gland that is consistent with
an adenoma.

26. Anteroposterior
radiographic view of the
right hand in a patient
with multiple endocrine
neoplasia syndrome type 1
(MEN1) and primary
hyperparathyroidism. This
image shows subperiosteal
bone resorption along the
radial aspects of the
middle phalanges
(arrows).

27. Other Tests
 Genetic testing
 Histologic Findings

28. Approach Considerations
 Hyperparathyroidism
 Surgery is the definitive treatment. Subtotal (3.5
glands)or total parathyroidectomy with forearm
autotransplantation is performed with an open
bilateral neck exploration. The recommended timing
of surgery in a patient is controversial. Recurrent
hypercalcemia is common. Transcervical thymectomy
may need to be performed at the same time, owing to
the mortality associated with malignant carcinoid
tumors of the thymus.

29.  Gastrinoma
 Inhibition of acid hypersecretion is achieved with
proton pump inhibitors. Histamine receptor
antagonists may be added.
 Nonmetastatic gastrinomas located in the pancreas
are rare but can be surgically excised.
 Removal of tumors larger than 2 cm in diameter
reduces the frequency of liver metastasis, which is an
important prognostic factor.Surgical cure of multiple
duodenal gastrinomas is difficult
 Other novel approaches, such as chemotherapeutic
agents or hormonal therapy with somatostatin
analogs, can be considered to treat disseminated
gastrinomas.

30.  Insulinoma
 Surgical removal of the tumor is the treatment of
choice.
 Unresectable tumors can be treated with diazoxide or
octreotide. Chemotherapeutic agents or hepatic artery
embolization has been used to treat metastatic disease
 Some authors recommend subtotal pancreatectomy
(80% or more of the pancreas) in patients with
multiple tumors or when the tumor is not localized.

31.  Glucagonomas
 Surgical removal of the tumor is the treatment of choice.
Usually, this involves excision of the tail of the pancreas.
However, often times, metastases have already occurred at the
time of diagnosis. Somatostatin analogs (lanreotide or
octreotide), chemotherapeutic agents, and hepatic artery
embolization have also been used
 Vasoactive intestinal polypeptide tumor (VIPoma)
 Somatostatin analogs control symptoms in 80% of cases,
although surgical cure should be attempted.
 Asymptomatic nonfunctioning pancreatic
neuroendocrine tumors
 A consensus regarding surgical indications has not been
established. The goal is to reduce mortality and morbidity
associated with metastatic disease while preserving pancreatic
tissue. Conflicting expert opinion suggests surgical removal of
tumors greater than 1 cm versus 2 cm.

32.  Pituitary tumors
 Treatment is similar to non-MEN1–associated pituitary
tumors. Prolactinomas are treated with bromocriptine or
cabergoline. Octreotide or lanreotide is used for
somatotrophinomas. Transsphenoidal tumor removal with
radiotherapy can be used if necessary.
 Carcinoid tumors
 If resectable, surgery is the treatment of choice. For
unresectable tumors, treatment with radiotherapy or
chemotherapeutic agents can be used. Somatostatin
analogs can help with symptoms and may shrink some
tumors.
 Cutaneous manifestations of MEN1
 Management is conservative for lipomas, facial
angiofibromas, and collagenomas. Local excision can be
performed if desired.

33. SOMATOSTATIN ANALOGS
 Used since 1980’s
 Hormone blocking agents that are synthetic somatostatin
derivatives (ex: octreotide and lanreotide)
 Octreotide acts primarily on somatostatin receptor
subtypes II and V. It inhibits growth hormone secretion
and has a multitude of other endocrine and nonendocrine
effects, including inhibition of glucagon, vasoactive
intestinal peptide, and GI peptides.
 Side effects: development of gallstones secondary to
inhibition of cholecystokinin release, pain at site, hypo or
hyperglycemia, rash, alopecia, fluid retention

35. Type 2 multiple endocrine
neoplasia (MEN 2)
 Sipple first described an association between thyroid
cancer and pheochromocytoma in 1961.
 The thyroid cancer found with pheochromocytoma
was discovered in 1965 to be a medullary carcinoma
characterized by stromal amyloid.
 In 1968, this familial constellation of pathology in
conjunction with parathyroid hyperplasia was
recognized as (MEN 2).
 the distinction between MEN 2A and MEN 2B was not
made until 1975

36.  Phenotype - MEN 2A patients do not have the
phenotypic abnormalities of mucosal neuromas and
marfanoid habitus found in MEN 2B patients
 Medullary thyroid carcinoma - MEN 2A patients have
a less virulent than do MEN 2B patients
 Parathyroid hyperplasia - MEN 2A patients may have,
which is exceedingly rare in MEN 2B patients
 A third subtype of MEN 2 is familial medullary thyroid
carcinoma only (FMTC only).

37. Etiology
 MEN 2 is a rare familial cancer syndrome caused by
mutations in the RET proto-oncogene localized to
10q11.2 .
 Inherited as an autosomal dominant disorder,

38. Pathophysiology and presentations
Medullary thyroid carcinoma
 Virtually in all patients with MEN 2A.
 the first expressed abnormality and usually occurs in the second or third
decade of life.
 typically bilateral and multicentric, in contrast to sporadic medullary
thyroid carcinoma, which is unilateral.
Pheochromocytoma
 Pheochromocytomas are present in 50% of MEN 2A patients.
 bilateral in 60-80% of patients, compared with 10% of patients with sporadic
pheochromocytomas.
 diagnosed at the same time as medullary thyroid carcinoma or several years
later (with both occurring primarily in the second or third decade).
 nearly all benign.
 Even so, these lesions can cause a life-threatening hypertensive episode or
arrhythmia.
Parathyroid hyperplasia
 in nearly half of patients with MEN 2A but are less common than
pheochromocytomas.
 can be clinically silent.
.

39.  Hypertension
 If pheochromocytomas develop, an increase in blood
pressure and heart rate may be the only signs. These
increases can be chronic or episodic. Some patients have
episodes of sweating and headaches.
 Diarrhea
 If a patient has medullary thyroid carcinoma
 This may be related to elevated prostaglandin or
calcitonin levels.
 Pruritic skin lesions
 Cutaneous lichen amyloidosis in MEN 2A patients
manifests as multiple pruritic, hyperpigmented,
lichenoid papules in the scapular area of the back..

41.  The marfanoid habitus of high-arched palate,
pectus excavatum, bilateral pes cavus, and scoliosis are
observed in MEN 2B patients.
 Neuromas on the eyelids, conjunctiva, nasal and
laryngeal mucosa, tongue, and lips are frequent
findings.
 Patients also have prominent, hypertrophied lips
leading to a characteristic facies. Localized pruritus
appears over the upper back in MEN 2B patients.

43. Approach Considerations
 Perform genetic screening for RET mutations in all index
patients. If a mutation is identified, also screen family
members who are at risk.
 baseline calcitonin levels and of serum calcium and
parathyroid hormone (PTH) levels, along with urine
collection for catecholamines and metanephrine
concentrations.
 Imaging Studies
 Perform computed tomography (CT) scanning or magnetic
resonance imaging (MRI) of the adrenals.
 A metaiodobenzylguanidine (MIBG) scan is useful for
localizing pheochromocytomas

44.  Fine-needle aspiration
 Avoid the removal of cells from thyroid masses for
cytology in patients with type 2 multiple endocrine
neoplasia (MEN 2) who have had their diagnosis
previously confirmed by either genetic analysis or
elevated calcitonin levels as biopsy increases the
possibility of tumor spread

45. Management of comlications
 Pheochromocytoma
Preoperatively, prepare patients by treating them with an
alpha-blocker or a tyrosine hydroxylase inhibitor, such as
metyrosine, for 1-2 weeks, after which administration of a
beta-blocker can be considered
 Hypercalcemia
Patients presenting with severe hypercalcemia should first be
hydrated, after which they should be treated with
furosemide. If they remain severely hypercalcemic,
consider treatment with calcitonin, glucocorticoids, or
bisphosphonates (such as pamidronate).

46. Treatment strategy
 Surgical treatment is the standard with replacement
therapy after the surgey
 Patients require hormone replacement following total
thyroidectomy and bilateral adrenalectomy or when
they have postoperative hypoparathyroidism. In
addition, patients who develop postoperative
hypoparathyroidism need supplemental calcium
and/or vitamin D.
 The corticosteroid cortisone and the mineralocorticoid
fludrocortisone acetate can be used in combination in
patients suffering from adrenocortical insufficiency.