ENDOCRINE

PATHOLOGY
内分泌病理
CLIN A/PROF LEOW WEI QIANG
SENIOR CONSULTANT
DEPARTMENT OF ANATOMICAL PATHOLOGY
SINGAPORE GENERAL HOSPITAL
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Overview of Endocrine Organs
Endocrine signals, a form of cell cross talk
PITUITARY
GLAND
垂体
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 PITUITARY

 Located at the base of the brain

within the sella.

 Lies beneath the hypothalamus to

which it is attached by a stalk.

 Anterior (adenohypophysis) and

posterior (neurohypophysis)
components.
Command Centre
Normal Anterior Pituitary
 FUNCTIONAL STATES

Hypofunctional states (hypopituitarism)

Ischaemic injury, inflammation, surgery, radiation

Hyperfunctional state (hyperpituitarism)

Adenomas

Non-functional
 Null adenomas
 HYPOPITUITARISM

Sheehan syndrome:
– postpartum necrosis of anterior pituitary following
postpartum haemorrhage
– posterior pituitary spared because of different blood
supply
 PITUITARY ADENOMAS

Functioning or non-functioning
Localised symptoms – due to mass effect of tumour
(compression on optic chiasm leads to bitemporal
hemianopia)
Systemic symptoms – due to effects of hormones on
target tissue
Macroadenomas (>1cm) OR Microadenomas (<1cm)
 PITUITARY ADENOMAS
Functioning or non-functioning
Localised symptoms – due to mass effect of tumour
(compression on optic chiasm leads to bitemporal
hemianopia)
Systemic symptoms – due to effects of hormones on
target tissue
Macroadenomas (>1cm), microadenomas (<1cm)
 CLASSIFICATION OF ADENOMAS

TSH cell adenoma

ACTH cell adenoma
Prolactin (PRL) cell adenoma

Growth hormone (GH) cell adenoma

Gonadotroph (FSH and LH) cell adenoma
 often silent and called null cell adenoma
 CLASSIFICATION OF ADENOMAS

TSH – GRAVES’ DISEASE

ACTH – CUSHING’S DISEASE
PRL – GALACTORRHEA, AMENORRHEA

GH – ACROMEGALY
FSH and LH – LOCAL MASS EFFECTS
 ACROMEGALY

Richard Kiel, who played Jaws, from

James Bond movies.
 Posterior pituitary gland

Derived from a downgrowth of the hypothalamus and

secretes 2 hormones: ADH and oxytocin.

Oxytocin stimulates uterine smooth muscle contraction

during childbirth and causes ejection of milk during
lactation.
 Posterior pituitary gland

 ADH is secreted in response to raised plasma osmolarity and induces conservation of body
water by increasing the permeability of renal collecting ducts resulting in increased
resorption of water

 ADH deficiency (diabetes insipidus)

 Causes include trauma, neoplasm, inflammation.
 Leads to excretion of large volumes of dilute urine, raised serum osmolality, thirst & polydipsia.

 Syndrome of inappropriate ADH (SIADH) secretion

 Causes include ectopic ADH secretion by neoplasms (small cell carcinoma of lung), injury to
hypothalamus or neurohypophysis
 Leads to hyponatremia, cerebral oedema
THYROID
GLAND
甲状腺
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Homeostasis in the hypothalamus-pituitary-thyroid
axis and mechanism of action of thyroid
hormones. Secretion of thyroid hormones (T3 and
T4) is controlled by trophic factors secreted by
both the hypothalamus and the anterior pituitary.
Decreased levels of T3 and T4 stimulate the
release of thyrotropin-releasing hormone (TRH)
from the hypothalamus and thyroid-stimulating
hormone (TSH) from the anterior pituitary, causing
T3 and T4 levels to rise. Elevated T3 and T4
levels, in turn, suppress the secretion of both TRH
and TSH. This relationship is termed a negative-
feedback loop. TSH binds to the TSH receptor on
the thyroid follicular epithelium, which causes
activation of G-proteins, release of cyclic AMP
(cAMP), and cAMP-mediated synthesis and
release of thyroid hormones (T3 and T4). In the
periphery, T3 and T4 interact with the thyroid
hormone receptor (TR) to form a hormone-
receptor complex that translocates to the nucleus
and binds to so-called thyroid response elements
on target genes initiating transcription.
Homeostasis in the hypothalamus-pituitary-thyroid
axis and mechanism of action of thyroid
hormones. Secretion of thyroid hormones (T3 and
T4) is controlled by trophic factors secreted by
both the hypothalamus and the anterior pituitary.
Decreased levels of T3 and T4 stimulate the
release of thyrotropin-releasing hormone (TRH)
from the hypothalamus and thyroid-stimulating
hormone (TSH) from the anterior pituitary, causing

NEGATIVE
T3 and T4 levels to rise. Elevated T3 and T4
levels, in turn, suppress the secretion of both TRH
and TSH. This relationship is termed a negative-

FEEDBACK
feedback loop. TSH binds to the TSH receptor on
the thyroid follicular epithelium, which causes
activation of G-proteins, release of cyclic AMP
(cAMP), and cAMP-mediated synthesis and
release of thyroid hormones (T3 and T4). In the
periphery, T3 and T4 interact with the thyroid
hormone receptor (TR) to form a hormone-
receptor complex that translocates to the nucleus
and binds to so-called thyroid response elements
on target genes initiating transcription.
 Role of Thyroid Hormones

Up-regulation of carbohydrate and lipid catabolism

and stimulation of protein synthesis in a wide range
of cells.

The net result of these processes is an increase in the

basal metabolic rate.
 (1) MULTINODULAR GOITRE

Due to impaired thyroid

hormone synthesis, there is
compensatory increase in
TSH from the pituitary,
leading to follicular
epithelial hyperplasia.
 (1) MULTINODULAR GOITRE
Iodine deficiency
 Endemic type (dietary)
 Sporadic type
• females / puberty - increased T4
requirements
• hormonal dysgenesis - diet and
hereditary enzyme defects that
interfere with thyroid hormone
synthesis
大颈项
Multinodular goiter. The gland is coarsely nodular and contains areas of fibrosis and
cystic change. Note the brown gelatinous colloid characteristic of this condition
("colloid goiter").
Colloid-rich follicles lined by
flattened inactive epithelium
and areas with follicular
epithelial hypertrophy and
hyperplasia
Fibrosis, cystic change,
hemorrhage, calcification
Mass effects and
hyperthyroidism
 (2) AUTOIMMUNE THYROIDITIS

Spectrum of conditions leading to hypofunctional

states or hyperfunctional states.

Hashimoto thyroiditis
Graves’ disease
 HASHIMOTO THYROIDITIS
 Adult – 45 to 65 years
 F:M = 10:1 to 20:1
 Autoimmune - Ab directed against thyroglobulin, TSH receptors and other
follicular cell antigens
 Central role of T Helper cell in pathogenesis
 Painless enlargement of thyroid with hypothyroidism
 May have earlier hyperthyroidism or thyrotoxicosis - due to destruction of
follicles with release of thyroxine
 Symptoms of hypothyroidism include slowing of physical and mental activity,
fatigue, apathy, cold intolerance, overweight, constipation, decreased sweating.
 HASHIMOTO THYROIDITIS

DESTROYS THYROID FOLLICULAR CELLS!

NORMAL THYROID
 HASHIMOTO’S

• Extensive lymphocytic infiltrate with germinal center formation.

• Atrophic follicles with oncocytic change (abundant eosinophilic cytoplasm).
 GRAVES’ DISEASE
 Age 20-40s
 F:M = 7:1
 Autoimmune disorder
 Autoantibodies to the TSH receptors lead to chronic activation
and hyperfunctional state, with increased thyroxine secretion,
hence hyperthyroidism or thyrotoxicosis

STIMULATES THYROID FOLLICULAR CELLS!

 GRAVES’ DISEASE
Commonest cause of hyperthyroidism or
thyrotoxicosis
State of increased thyroxine action
Opthhalmopathy / Exophthalmos
Sometimes skin changes in shins – pretibial
myxoedema – dry waxy skin due to deposits of mucin
Diffuse thyroid enlargement (diffuse toxic goitre)
Opthalmopathy- oedematous tissues in orbit due to glycosaminoglycan deposits
 GRAVES’ DISEASE - hyperthyroidism
Increased actions of T4 and T3
Heat intolerance and sweatiness
Palpitations and increased heart rate
Weight loss or poor weight gain despite increased
appetite
Tremors, irritability
Diarrhoea
Myopathy (muscle weakness) - rare
 Graves’ disease –
Irregularly shaped follicles
with scalloping of colloid

Papillary infoldings
and scalloping of
colloid
 (3) THYROID NEOPLASMS

Presentation - solitary thyroid nodule

Mostly benign, 1% malignant
Young patients - more likely malignant
Male patients - more likely malignant but overall still
more common in females
 BENIGN, FOLLICULAR ADENOMA

Follicular adenoma of the thyroid (most common benign

neoplasm). A solitary, well-circumscribed nodule is seen.
Well defined capsule, composed of uniform follicles.
A BENIGN FOLLICULAR CELL
 THYROID CARCINOMAS
Papillary thyroid carcinoma (80%)
Follicular carcinoma (15%)
Medullary carcinoma (5%)
Anaplastic carcinoma (<5%)

Others - lymphomas, sarcomas (rare)

 THYROID CARCINOMA - Risk factors

Increases with age – plateaus after age 50 yrs

Females more than males
Family history
Genetic predisposition – MEN syndromes
History of neck irradiation
Iodine deficiency – follicular carcinoma
 Papillary thyroid carcinoma (PTC)

Named so, as the classical histological appearance

shows branching papillae with a fibrovascular stalk
covered by single to multiple layers of cuboidal or
columnar epithelial cells.

These papillae differ from those seen in areas of

hyperplasia in being more complex and having dense
fibrovascular cores.
 Papillary thyroid carcinoma (PTC)
Many variants described such as follicular, sclerosing,
cribriform-morular, solid etc.
Diagnosis of papillary carcinoma is based on nuclear
features, even in the absence of papillary architecture.
 Papillary thyroid carcinoma (PTC)
 PTC nuclei contain finely dispersed chromatin which imparts an
optically clear or empty appearance, giving rise to the
designation “ground-glass” or “orphan Annie eye” nuclei.

 In addition, invaginations of the cytoplasm in cross-sections give

the appearance of intranuclear pseudoinclusions and nuclear
membrane irregularity creates nuclear grooves.
 Papillary thyroid carcinoma (PTC)

 Concentrically calcified structures - psammoma bodies, usually

within the cores of papillae.

 They are usually not found in follicular and medullary carcinomas,

so are a strong indicator of papillary carcinoma when present in
FNAC material.

 Metastases to adjacent cervical lymph nodes occur in up to 50% of

cases.
 Follicular thyroid carcinoma (FTC)

• This is a follicular adenoma gone bad.

• Composed of well differentiated follicular cells showing obvious
capsular and / or blood vessel invasion and lacking PTC-type
nuclear changes.
• Multiple foci of vascular invasion predicts a worse outcome.
• Distant metastases (eg to lungs, bone) more common than regional
lymph node involvement.
 Medullary thyroid carcinoma (MTC)

• MTCs are derived from parafollicular cells, or C cells, of the thyroid

and account for approximately 5% of thyroid neoplasms.
• Parafollicular cells are neuroendocrine in origin and secrete
calcitonin, the measurement of which plays an important role in the
diagnosis and postoperative follow-up of patients.
• About 70% of MTCs arise sporadically, with the rest occurring in the
setting of MEN syndrome or familial disease (familial medullary
thyroid carcinoma).
• Associated with RET mutations.
•Tan fleshy appearance.
•Composed of polygonal to spindle cells which form nests, trabeculae and even follicles.
•Amyloid deposits from altered calcitonin molecules.
•Calcitonin can be demonstrated by immunohistochemical methods in tumour cells and
stroma.
 Anaplastic carcinoma
Undifferentiated tumour composed of anaplastic cells
(large pleomorphic giant cells, spindle cells).

Aggressive, mortality close to 100%.

PARATHYROID
GLAND
甲状旁腺

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 Parathyroid glands

Most individuals have 4 parathyroid glands.

The glands are composed predominantly of chief cells
which secrete parathyroid hormone (PTH).
PTH mobilises calcium from bone, increases renal
tubular resorption of calcium, promotes production of
1,25 dihydroxyvitamin D1 in the kidney and enhances
phosphate excretion by the kidney.
PROBLEMS WITH INCREASED PTH
 Parathyroid glands

Hypoparathyroidism (rare)

Surgical removal during thyroidectomy

Congenital absence

Autoimmune destruction
 Parathyroid glands

Hyperparathyroidism can be primary, secondary or

tertiary.
Primary hyperparathyroidism may be due to an adenoma in one of the
parathyroid glands (75-80%), hyperplasia of all of the glands (10-15%)
or parathyroid carcinoma (<5%).
Secondary hyperparathyroidism is due to chronic depression of serum
calcium level with renal failure being the most common cause.
Tertiary hyperparathyroidism occurs after a prolonged period of 2o
hyperparathyroidism, with autonomous persistent parathyroid
stimulation.
 Parathyroid adenoma

 Confined to single gland.

 Composed of chief cells, with compressed non-neoplastic
parathyroid gland at periphery.
 Fibrous capsule.
Parathyroid hyperplasia
 Parathyroid carcinoma

 Grey-white irregular masses, composed of malignant parathyroid cells.

 Invasion of surrounding tissues and metastasis is important in
diagnosis.
PANCREAS
(Endocrine)
胰腺
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Islet of Langerhans
 Islet of Langerhans
 Composed of beta, alpha, delta
and PP (pancreatic polypeptide)
cells.

 Beta cells – insulin

 Alpha cells – glucagon
 Delta cells – somatostatin
 PP cells – vasoactive intestinal
peptide (VIP)
Glucagon- induce gylcogenolysis in liver and
increases blood glucose.

Somatostatin- suppress insulin and glucagon release.

Vasoactive Intestinal Peptide (VIP)- stimulates

secretion of gastric and intestinal enzymes, inhibit
intestinal motility.
Metabolic actions of insulin in striated muscle, adipose tissue, and liver
 Diabetes Mellitus
 Considered by many an epidemic in urbanised areas.
 Metabolic disorder characterized by hyperglycemia.

 Type 1- deficiency of insulin due to beta cell destruction,

autoimmune (10%).

 Type 2- peripheral resistance to insulin action and inadequate

compensatory response of insulin secretion (80-90%).
 Characteristic Type 1 Type 2

Incidence 10% 80-90%

Diabetogenic and
HLA
Genetics obesity related
genes
genes
Onset Youth Maturity
Beta cell destruction? Yes No
Insulin deficiency Yes No
Inadequate insulin utilization No Yes
Patients usually obese? No Yes
Insulin dependent Yes No
Hyperglycemia prominent? Yes Yes
Polyuria, polydipsia, and polyphagia prominent? Yes Yes
Acidosis and coma possible? Yes No
Dehydration and coma possible? No Yes
 Pathogenesis of type 2 diabetes
mellitus. Genetic predisposition
and environmental influences
converge to cause insulin
resistance. Compensatory beta-
cell hyperplasia can maintain
normoglycaemia, but eventually
beta-cell secretory dysfunction
sets in, leading to impaired
glucose tolerance and eventually
frank diabetes. Rare instances of
primary beta-cell failure can
directly lead to type 2 diabetes
without a state of insulin
resistance.
 Diabetes Mellitus
Complications arise due to :
Formation of advanced glycation end products (AGEs).

Activation of protein kinase C.

Disturbance in polyol (sugar alcohols) pathways.

Long-term complications of diabetes
 Diabetes Mellitus
Diabetic vascular disease:
accelerated atherosclerosis (large and medium sized arteries).

hyaline arteriolosclerosis (hyaline thickening of arteriole

wall).

Diabetic microangiopathy (diffuse thickening of basement

membrane affecting capillaries, renal tubules, Bowman
capsule, peripheral nerves).
 Small or Large Blood Vessels Complications
- Blindness
- Kidney damage
Small Blood Vessel Disease - Nerve damage
- Susceptibility to infection
- Delayed healing
- Atherosclerosis
- Myocardial infarction
- Strokes
Large Blood Vessel Disease - Leg/feet ulcers
- Leg/feet gangrene
- Leg/feet amputation

Type of Diabetes Mellitus Treatment

Type I - Insulin

- Weight reduction
Type II - Oral hypoglycaemic agents
- Insulin
Diabetes Mellitus is one of the common
causes of end stage renal failure.
 Morphological changes in Diabetes

Lesions in the pancreas are inconstant and rarely of

diagnostic value. One or more of the following
alterations may be present:

 Reduction in the number and size of islets. This is most often seen in
type 1 diabetes, particularly with rapidly advancing disease.
 Leukocytic infiltrates in the islets (insulitis) are principally composed of
lymphocytes and macrophages, more severe in type 1.
 Amyloid deposition within islets in type 2 diabetes begins in and
around capillaries and between cells. In advanced stages, the islets may
be virtually obliterated.
Insulitis Amylin or islet amyloid polypeptide
 Acute complications of DM
Diabetic Coma

Diabetic KetoAcidosis - IDDM type 1

Hyperosmolar Hyperglycemic NonKetotic - NIDDM type 2

PANCREATIC NEOPLASMS (endocrine)
Known as Pancreatic Neuroendocrine Tumours
(PanNET)
Can be non-functional or functional.

Insulinoma - most common

Gastrinomas
Others (somatostatin, VIPoma) rarer
 Insulinoma
Insulinomas are most often found within the pancreas
and are generally benign. Most are solitary, although
multiple tumors may be encountered.

Malignant change, making up only about 10% of

cases, are diagnosed on the basis of local invasion and
distant metastases.
 Insulinoma
Solitary tumors are usually small (often <2 cm in
diameter) pale to red-brown nodules, may be
encapsulated.

Histologically looks like giant islets containing cords of

monotonous cells.

Deposition of amyloid in the extracellular tissue is a

characteristic feature.
Pancreatic neuroendocrine tumor (PanNET), also called islet cell tumor.
The neoplastic cells are monotonous in appearance and demonstrate
minimal pleomorphism or mitotic activity. There is abundant amyloid
deposition, characteristic of an insulinoma.
 Gastrinomas
 Can arise in the duodenum, peripancreatic soft tissue or in the pancreas.
 Marked hypersecretion of gastrin, causing hypersecretion of gastric acid
and severe peptic ulceration (Zollinger-Ellison syndrome).
 Over half of gastrin-producing tumors are locally invasive or have already
metastasized at the time of diagnosis.
 In approximately 25% of patients, gastrinomas arise in conjunction with
other endocrine tumors, as part of the MEN-1 syndrome.
 MEN-1–associated gastrinomas are frequently multifocal, while sporadic
gastrinomas are usually single.
ADRENAL
GLAND
肾上腺
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Constitutes the peripheral 80% of
the gland.
3 main classes of steroid hormones
are secreted: glucocorticoids,
mineralocorticoids and sex
steroids.
 Cortisol, a glucocorticoid
Cortisol is also known as ‘stress hormone’.
Glucocorticoids increase protein breakdown and fat loss
from the extremities, but promotes fat accumulation in
the trunk, neck and face.
Glucocorticoids also have effects on the immune system.
Synthesis and secretion of glucocorticoids is under
negative feedback control by ACTH.
 Cushing’s syndrome (too much cortisol!)
Cushing’s syndrome is a hormonal disorder caused by
elevated levels of cortisol in the blood.
Cushing’s disease refers to one specific cause of the
syndrome (hypothalamic-pituitary disease associated
with ACTH hypersecretion, usually due to pituitary
microadenoma).
Most common cause of Cushing’s syndrome is
exogenous steroid administration.
 ADRENAL CORTICAL HYPERPLASIA

• Diffuse hyperplasia of both glands, thickened cortex.

• Microscopically, expanded hyperplastic cortex with vacuolated “lipid-rich” cells,
which accounts for the yellow colour of diffusely hyperplastic glands.
 Adrenocortical adenoma / carcinoma
Primary adrenocortical neoplasms causing Cushing’s
syndrome may be malignant or benign.
Adrenocortical adenomas are yellow tumours
surrounded by thin or well-developed capsules, and
most weigh less than 30g.
Microscopically, they are composed of cells that are
similar to those encountered in the normal zona
fasciculata.
 Adrenocortical adenoma / carcinoma
Adrenocortical carcinomas associated with Cushing’s
syndrome tend to be larger than the adenomas. These
tumors are unencapsulated masses frequently
exceeding 200 to 300g in weight, with histologic
characteristics of cancer such as invasion and
pleomorphic cells.
Adrenocortical adenoma / carcinoma
 Aldosterone, a mineralocorticoid
Aldosterone is the most important mineralocorticoid.
Its function is to maintain intravascular volume.
 Conn’s syndrome (too much aldosterone!)
• May be primary or secondary to an extra-adrenal cause.

• Primary hyperaldosteronism stems from an autonomous

overproduction of aldosterone, with resultant suppression of
the renin-angiotensin system and decreased plasma renin
activity.

• Blood pressure elevation is the most common manifestation

of hyperaldosteronism.
 Primary Conn’s syndrome
Bilateral nodular hyperplasia of the adrenal glands
accounts for about 60% of cases, pathogenesis unclear.

 Adrenocortical neoplasm, either an aldosterone-producing

adenoma (35%), or rarely a carcinoma. This is known as
Conn syndrome.

Rarely, familial, resulting from genetic defect.

Adrenocortical adenoma

Uniform cells, occasional pleomorphism.

Adrenocortical carcinoma
 Androgen, a sex steroid
 Sex steroids play a secondary role in the development of
male and female sexual characteristics
 Gonadal organs

Ovaries - sex steroids oestrogen and progesterone

(under the influence of FSH and LH from pituitary)
are essential for development of female sexual
characteristics, ovulation and menstruation cycle,
pregnancy.

Testes - Leydig cells produce testosterone which

drives male sexual characteristics.
 Adrenal medulla
 Derived from embryonic neural crest and is part of the sympathetic nervous
system (fight or flight).
 Consists of neuroendocrine (chromaffin) cells and sympathetic nerve
endings.
 Main function of chromaffin cells is to synthesise and secrete catecholamines
(adrenaline and noradrenaline).
 Most significant disorders are neoplasms including phaeochromocytoma,
neuroblastoma and ganglioneuroma.
 Phaeochromocytoma
 Phaeochromocytomas are a rare cause of medically resistant but
surgically correctable hypertension.
 10% of phaeochromocytomas are extra-adrenal, occurring in the
retroperitoneum and the carotid body (aka paragangliomas).
 10% of sporadic adrenal phaeochromocytomas are bilateral; this
figure may rise to as high as 50% in cases that are associated with
familial syndromes.
 10% of adrenal phaeochromocytomas are biologically malignant,
defined by the presence of metastatic disease.
Composed of polygonal to spindle cells
compartmentalized into nests (Zellballen)
MULTIPLE
ENDOCRINE
NEOPLASIA

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MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROME

Proliferative lesions (hyperplasias, adenomas and

carcinomas) arising in multiple organs.

Younger age of onset.

Tumours are more aggressive and tend to recur after

resection.
MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROME

Inherited as autosomal dominant pattern.

MEN Type 1 (MEN1 tumour suppressor gene)
parathyroid hyperplasia, pancreatic endocrine tumours, pituitary
adenomas
MEN Type 2 (RET proto-oncogene mutation)
Type 2a – medullary thyroid cancer, adrenal
phaeochromocytoma, parathyroid hyperplasia
Type 2b – like 2a but no parathyroid involvement, but has
ganglioneuromas involving mucosal sites and marfanoid habitus
FEEDBACK
Lecturer
Dr Leow Wei Qiang
leow.wei.qiang@singhealth.com.sg
Topic
Endocrine Pathology
(including Pancreas)
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