PATHOLOGY OF ENDOCRINE

SYSTEM
DR.dr. Nia Kania Sp PA. (K)
Bagian patologi anatomi
Fakultas Kedokteran Lambung
Mangkurat
 SYSTIM
ENDOKREN
The Endocrine system is divided into
:
Endocrine organs dedicated to
production of hormones e.g.
pituitary,thyroid.etc
Endocrine components in clusters in
organs having mixed functions e.g.
pancreas, ovary, testes..
Diffuse endocrine system comprising
scattered cells within organs acting
locally on adjacent cells without entry
into blood stream
Disease divided into :

1- Diseases of overproduction of secretion

( Hyperfunction )
2- Diseases of underproduction
( Hypofunction )
3- Mass effects ( Tumors )

Correlation of clinical picture , hormonal

assays , biochemical findings , together
with pathological picture are of extreme
importance in most conditions.
PITUITARY GLAND
 PITUITARY GLAND
Pituitary in sella turcica,& weighs about 0.5gm.
Connected to the HYPOTHALAMUS with stalk.
Composed of :
A-ADENOHYPOPHYSIS- (80%)
Blood supply is through portal venous plexus
Hypothalamic-Hypophyseal feed back control
B- NEUROHYPOPHYSIS
From floor of third ventricle
Modified glial cells & axons hypothalamus.
Has its own blood supply.
CELLS & SECRETIONS :
A- Anterior pituitary ( Adenohypophysis )

1-Somatotrophs from acidophilic cells Growth

H.
2- Lactotrophs from chromophobe cells
Prolactin
3- Corticotrophs from basophilic cells
ACTH,MSH .
4- Thyrotrophs from pale basophilic cells TSH
5- Gonadotrophs from basophilic cells FSH, LH

B- Posterior pituitary ( Neurohypophysis )

1- Oxytocin
Anatomi hipophise
HYPERPITUITARISM & PITUITARY ADENOMA

In most cases, excess is due to

ADENOMA
arising in the anterior lobe.
Less common causes include :
* Hyperplasia
* Carcinoma
* Ectopic hormone production
* Some hypothalamic disorders
Pathogenesis of pituitary
adenomas :
Mutations in G-proteins ( subunit) in the GNAS1
gene on chromosome 20q13 lead to activation
40% of GH secreting adenomas & less in ACTH
G-proteins involved in signal transduction :

GDP G proteins GTP cAMP

Mutations GTPase
in subunit interfere with GTPase function
Mutations in RAS, overexpression in C- MYC & NM23
inactivation found in more aggressive tumor
Other mutations : MEN-1 gene ( Menin)
Features common to all pituitary
adenomas :
10% of all intracranial neoplasms & 25%
incidental 3% occur with MEN syndrome
30-50 years of age
Primary pituitary adenomas usually benign
May or may not be functional
If functional, the clinical effects are secondary to
the hormone produced.
More than one hormone may be produced by
same cell
Although most are localized, invasive adenomas
erode sella turcica & extend into cavernous &
sphenoid sinus
CLINICAL FEATURES of PITUITARY
ADENOMA:

1- Symptoms of hormone produced

2- Local mass effects :
i- Radiological changes
ii-Visual field abnormalities
iii-Elevated intracranial pressure
3- Hypopituitarism
4- Pituitary apoplexy
Mass effect of pituitary adenoma
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Morphology of pituitary
adenomas :
Well circumscribed,invasive in up to 30%
Size 1cm. or more, specially in
nonfunctioning
tumor
Hemorrhage & necrosis seen in large tumors
Microscopic picture :
Uniform cells, one cell type (monomorphism)
Absent reticulin network
Rare or absent mitosis
Sella turcica with pituitary adenoma
Uniform cells of pituitary adenoma
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Types of Pituitary Adenomas
Previously classified according to
histological
picture e.g :
Acidophilic Adenoma
Now according to
immunohistochemical
findings & clinical picture .. e.g.
Growth hormone secreting adenoma
Immunoperoxidase for GH
1- PROLACTINOMA :

30% of all adenomas, chromophobe or weakly

acidophilic
Functional even if small, but related to size
Other causes of prolactin include : estrogen
therapy, pregnancy, reserpine ,
hypothyroidism
Any mass in the suprasellar region may interfere
with normal prolactin inhibition Prolactin
( STALK EFFECT )
Mild elevation of prolactin does NOT always
indicate prolactin secreting adenoma !
Symptoms :

Galactorrhea
Amenorrhea
Decrease libido
Infertility
 2- Growth hormone secreting adenoma :
40% Associated with GNAS 1 gene mutation
Persistent secretion of growth hormone leads
to secretion of Insulin like GF symptoms
Composed of granular ACIDOPHILIC cells
May be mixed with prolactin secretion.
Symptoms delayed so adenomas are usually
large
Produce GIGANTISM or ACROMEGALLY
Other symptoms : diabetes, arthritis, large
jaw & hands, osteo porosis, BP, HF..etc
gigantisme
acromegali
3- Corticotroph cell adenoma
Usually microadenomas
Higher chance of becoming malignant
Chromophobe or basophilic cells
Functionless or Cushing s Disease ( ACTH )
Bilateral adrenalectomy or destruction may
result in aggressive adenoma:
Nelsons Syndrome
Corticotroph microadenoma
Macroadenoma
ICP
4- Non functioning adenoma 20%
silent or null cell ,nonfunctioning & produce
mass
effect only
5- Gonadotroph producing LH &FSH- ( 10-
15%)- Function silent or is minimal , late
presentation mainly mass effect produced.
Produce gonadotrophin subunit, - FSH & -
LH

6- TSH producing ,(1%) rare cause of

hyperthyroidism

7- Pituitary carcinoma - Extremely rare,

diagnosed only by metastases.
HYPOPITUITARISM :
Loss of 75% of ant. Pituitary Symptoms
Congenital or acquired, intrinsic or extrinsic
Symptoms include dwarfism, & effect of
individual hormone deficiencies. Loss of MSH
Decreased pigmentation
Acquired causes include :
1- Nonsecretory pituitary adenoma
2- Ischemic necrosis e.g.
SHEEHANS SYNDROME (post partum hmg.)
sickle cell anemia, DIC, Pituitary apoplexy
3- Iatrogenic by radiation or surgery
4- Autoimmune ( lymphocytic) hypophysitis
5- Inflammatory e.g sarcoidosis or TB ..
6- Empty Sella Syndrome : Radiological
term for enlarged sella tursica, with
atrophied or
compressed pituitary.
May be primary due to downward
bulge of arachnoid into sella floor
compressing pituitary.
Secondary is usually surgical.

7- Infiltrating diseases in adjacent bone

e.g. Hand Schuller Christian Disease

8- Craniopharyngioma
Craniopharyngioma :

* 1-5 % of intracranial neoplasms

* Derived from remnants of Rathkes Pouch
* Suprasellar or intrasellar ,often cystic with
calcification
* Children or adolescents most affected
* Symptoms may be delayed 20yrs( 50%)
* Symptoms of hypofunction or hyperfunction
of pituitary and /or visual disturbances,
diabetes insipidus
* Benign & slow growing
POSTERIOR PITUITARY SYNDROMES:
1-A- ADH deficiency causes Diabetes Insipidus
Excessive urination,dilute urine , due to
inability to reabsorb water from the
collecting tubules. Causes include head
trauma, tumors & inflammations in
pituitary
or hypothalamusetc.
B- Syndrome of inappropriate ADH secretion
Causes excessive resorption of water
hyponatremia e.g Small Cell CA of Lung
2-Abnormal oxytocin secretion :

Abnormalitis of synthesis & release

have not been associated with any
significant abnormality.
THYROID GLAND
 Development from evagination of
pharyngeal tissue into neck
Abnormal descent Lingual thyroid ,
subhyoid, substernal
Weight 15-20gm. Responsive to stress
Structure : varying sized follicles lined by
columnar epithelium , filled with colloid,
interfollicular C cells
Secretion of T3 & T4 is controlled by
trophic
factors from hypothalamus & ant.pituitary
THYROTOXICOSIS:
Hypermetabolic state caused by T4, T3.
A- Associated with hyperthyroidism:
Primary : Graves Disease
Toxic multinodular goiter
Toxic adenoma
Secondary : TSH secreting pit. adenoma
B- Not associated with hyperthyroidism :
Thyroiditis
Struma ovarii
Exogenous thyroxine intake
Clinical Picture related to Sympathetic
Stimulation

Constitutional symptoms : heat intolerance,

sweating, warm skin, appetite but weight

Gastrointestinal : hypermotility,
malabsorption

Cardiac : palpitation, tachycardia, CHF

Menstrual disturbances
 Neuromuscular : Tremor, muscle
weakness

Ocular : wide staring gaze, lid lag,

thyroid ophthalmopathy

Thyroid storm : severe acute symptoms

of sympathetic overstimulation

Apathetic hyperthyroidism : incidental

 Diagnosis of Hyperthyroidism :

Measurement of serum TSH ( ) + free T4

is the most useful screening test for
thyrotoxicosis

TSH level is normal or in secondary

thyrotoxicosis

In some patients , T3 but T4 normal or

Measurement of Radioactive Iodine uptake

is a direct indication of activity inside the
gland
Normal radioactive I uptake
HYPOTHYROIDISM :
Primary :
1- Loss of thyroid tissue due to surgery or
radiation Rx.
2- Hashimotos thyroiditis
3- Iodine deficiency specially in endemic areas
4- Primary idiopathic hypothyroidism
5- Congenital enzyme deficiencies
6- Drugs e.g. iodides, lithium..
7- Thyroid dysgenesis ( developmental )

Secondary :
Pituitary or hypothalamic failure
Hypothyroidism is commoner in endemic
areas of iodine deficiency
CRETINISM : hypothyroidism in infancy & is
related to the onset of deficiency .
If early in fetal life Mental retardation ,
short stature, hernia, skeletal abnormalities,

MYXEDEMA in adults Apathy, slow mental

processes, cold intolerence,accumulation of
mucopolysaccharides in subcutaneous
tissue

Lab.tests : TSH in primary hypothyroidism,

unaffected in others T4 in both.
THYROIDITIS :
Mostly autoimmune mechanisms
Microbial infection is rare
Types include :
1- Chronic lymphocytic ( Hashimotos )
thyroiditis
2- Subacute granulomatous ( de Quervain)
thyroiditis
3- Subacute lymphocytic thyroiditis
4- Riedel thyroiditis
5- Palpation thyroiditis
HASHIMOTOs THYROIDITIS :
Chronic Lymphocytic Thyroiditis

Autoimmune disease characterized by

progressive destruction of thyroid tissue
Commonest type of thyroiditis
Commonest cause of hypothyroidism in
areas
of sufficient iodine levels
F:M = 10-20 :1, 45-65 yrs.
Can occur in children
Pathogenesis :
A - T cell sensitization to thyroid antigens
1- Sensitized CD4 T cells Cytokine mediated
( IFN- )cell death inflammation,macrophage
activation
2- CD8+ cytotoxic T cell mediated cell death:
Recognition of AG on cell killed
3- Presence of thyroid AB Antibody
dependent
cell mediated cytotoxicity by NK cells
B- Genetic predisposition :
in relatives of 1st.degree
Association with HLA DR 3 & DR- 5
Morphology:

Gland is a smooth pale goitre,

minimally nodular, well demarcated.
Microscopically :
- Dense infiltration by lymphocytes &
plasma cells
- Formation of lymphoid follicles, with
germinal centers
- Presence of HURTHLE CELLS
- With or without fibrosis
 Clinically :

Painless symmetrical diffuse goiter

May show initial toxicosis
( Hashitoxicosis ).
Later marked hypothyroidism.
Patients have risk of B-Cell
lymphoma
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SUBACUTE GRANULOMATOUS
THYROIDITIS :
Middle aged , more in females. Viral
etiology ?
Self-limited (6-8w)
Acute onset of pain in the neck , fever,
ESR, WBC
Transient thyrotoxicosis.
Morphology :
Firm gland.
Destruction of acini leads to mixed inflammatory
infiltrate.
Neutrophils , Macrophages & Giant cells &
formation of granulomas
SUBACUTE LYMPHOCYTIC
THYROIDITIS : (Silent)
Middle aged females & post partum patients
Probably autoimmune with circulating AB
May recur in subsequent pregnancies
May progress to hypothyroidism
Histology similar to Hashimotos thyroiditis
without Hurthle cell metaplasia
Reidels Thyroiditis
Dense fibrosis without prominent inflammation
? Considered as fibromatosis rather than thyroiditis
GRAVES DISEASE :

Commonest cause of endogenous

hyperthyroidism
Age 20- 40 yrs.,
M: F ratio is 1: 7
More common in western races
Main features of GRAVES DISEASE :

1 - Thyrotoxicosis with smooth symmetrical

enlargement of thyroid
2 - Infiltrative ophthalmopathy with
exophthalmus in 40%
3- Pretibial myxedema in a minority

Lab findings : T4, T3 , TSH

Radioactive study: Diffuse uptake of
radioactive I
Pathogenesis of GRAVES DISEASE :
Genetic etiology + Autoimmune processes
GENETIC EVIDENCE :
May be familial
60% concordance in identical twins
Susceptibility is associated with
HLA-B8 & - DR3
May exist with other similar diseases e.g.
SLE, Pernicious anemia, Diabetes type I,
Addisons dis.
IMMUNE MECHANISMS :
Antibodies to thyroid peroxisomes & thyroglobulin
Patients develop autoantibodies to TSH receptor
Thyroid Stimulating Immunoglobulin ( TSI)
binds to TSH receptor thyroxin ***
Thyroid Growth Stimulating Immunoglobulin
(TGI) proliferation of thyroid epithelium
TSH binding inhibitor immunoglobulins (TBIIs)
prevent TSH from binding to receptor
Both stimulation & inhibition may coexist
Morphology :

Smooth enlargement of gland with

diffuse hyperplasia & hypertrophy
Lining epithelium of acini :
Tall & hyperplastic papillae
Colloid :
Minimal thin colloid with scalloped
edge
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Changes in Extrathyroid tissue :

Generalized lymphoid hyperplasia

Ophthalmopathy : Edematous orbital

muscles &infiltration by lymphocytes
followed by fibrosis

Thickening of skin & subcutaneous tissue

Accumulation of glycosaminoglycans
which
are hydrophilic
 Result :
Displacement of eyeball &
exophthalmus redness, dryness,
ulceration, infection in conjunctiva
Cause :
Expression of aberrant TSH receptor
responding to circulating anti TSH
receptor AB inflammatory
lymphocytic reaction
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DIFFUSE NONTOXIC & MULTINODULAR GOITRE
GOITER = Enlargement of thyroid
Most common cause is iodine
deficiency impaired hormone synthesis
TSH hypertrophy & hyperplasia of
follicles Goiter
Endemic : 10% of population have
goiter
Sporadic : 1- Physiological demand
2- Dietary intake of excessive
calcium & cabbagesetc
3- Hereditary enzyme defects
MORPHOLOGY :
Initially diffuse nodular with
degenerative changes: colloid cysts,
hemorrhage, fibrosis, calcification
If large may extend retrosternally
Pressure symptoms are a common
complaint
Picture is that of varying sized follicles,
hemorrhage , fibrosis , cysts, calcification
Patient is often EUTHYROID. but may be
toxic or hypofunctioning.
G
O
I
T
E
R
Normal radioactive I uptake
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NODULES in the thyroid :
Nodules in thyroid may be multiple or
solitary

Any solitary nodule in the thyroid has to be

investigated as some are neoplastic.
Investigations include FNA , Radioactive image
technique, Ultrasound, & (T4,T3 & TSH ) levels

HOT nodule takes up radioactive substance

( functional)
COLD nodule does not it take up
( nonfunctional )
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General rules of nodules in the thyroid :
1- Solitary nodule is MORE likely to be
NEOPLASTIC than multiple

2- Hot nodules are more likely to be BENIGN

3- Not every cold nodule is malignant .

Many are nonfuctioning adenomas, or
colloid
cysts , nodules of nodular goitre.etc
Up to 10% of cold nodules prove to be
malignant.
4- Nodules in younger patients are more
likely to be NEOPLASTIC

5- Nodules in males are more likely to be

NEOPLASTIC .

6- History of previous radiation to the

neck is associate with increased risk of
malignancy
NEOPLASMS of the THYROID :
ADENOMAS:
Usually single.
Well defined capsule
Commonest is follicular Hurthle cell
change
May be toxic
Size 1- 10cm. Variable colour
Activating somatic mutation in TSH receptor
is identified leading to overproduction of
cAMP
20% have point mutation in RAS oncogene
 Microscopical Picture :
1- Uniform follicles , lined by cuboidal epithelial
cells.
2- Focal nuclear pleomorphism, nucleoli .
( Endocrine atypia )
3- Presence of a capsule with tumor compressing
surrounding normal thyroid outside .
* Integrity of capsule is important in differentiating
adenoma from well differentiated follicular
carcinoma.
Capsular and/ or vascular invasion Carcinoma
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Adenoma with intact capsule 2005 Elsevier
Capsular invasion)
CARCINOMAS of THYROID :

Incidence about 1-2% of all malignancies.

Wide age range ,depending on type.
Generally commoner in females, but in
tumors occurring in children or elderly ,
equal incidence in both sexes.
Most are derived from follicular cells
Few are derived from C cells
TYPES of THYROID CARCINOMA :
1- Papillary Carcinoma ( 75- 85% ),any age,but
usual type in children.
2- Follicular Carcinoma ( 10- 20% )More in middle
age
3- Medullary Carcinoma ( 5% ) age 50-60 but
younger
in familial cases with MEN syndrome
4- Anaplastic Carcinoma ( 5% ) , old age

Presenting symptom is usually a mass , maybe

incidental in a multinodular goitre specially
papillary, & follicular
 Pathogenesis of Thyroid Cancer :
1- Genetic lesions :
Most tumors are sporadic
Familial is mostly Medullary CA , Papillary CA
Papillary CA :
Chromosomal rearrangement in tyrosin
kinase receptor gene (RET) on chr.10q11
ret/PTC tyrosine kinase activity
( 1/5 of cases specially in children)
Point mutation in BRAF oncogene (1/3-1/2)
 Follicular Carcinoma :
RAS mutation in of cases OR
PAX8- PPAR 1 fusion gene in 1/3 of
cases
Medullary Carcinoma :
RET mutation Receptor activation
Anaplastic Carcinoma :
Probably arising from
dedifferentiation of follicular or
papillary CA inactivation of P53
2- Environmental Factors :
Ionizing radiation specially in first two
decades
Most common is Papillary CA. with RET
gene rearrangement
3- Preexisting thyroid disease :
Incidence of thyroid CA is more in
endemic areas
Long standing multinodular goiter
Follicular CA
Hashimotos thyroiditis Papillary CA &

B cell lymphoma
 TYPES OF THYROID CARCINOMAS
PAPILLARY CARCINOMA :
Cold on Scan by radioactive Iodine

Solitary or multifocal

Solid or cystic, calcification

Composed of papillary architecture

Less commonly Follicular Variant

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Diagnosis based on NUCLEAR
FEATURES
Nuclei are clear (empty) ,with grooves &
inclusions ( Orphan Annie nuclei)

Psammoma bodies
Metastases mainly by L.N., sometimes
from
occult tumor
Hematogenous spread late & prognosis is
GOOD
FNA of Papillary CA (nuclear changes)
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Psammoma body in Papillary CA
FOLLICULAR CARCINOMA :
Usually cold but rarely functional ( warm )

Well circumscribed with thick capsule

(minimally invasive) or diffusely infiltrative

Composed of follicles , sometimes of

Hurthle Cells

Diagnosis is based on CAPSULAR &

VASCULAR invasion
 Metastasize usually by blood Lungs,
Bone, Liver ..etc.

Treatment by surgery Radioactive

Iodine Thyroxin

Prognosis is not as good as papillary

except in minimally invasive very well
differentiated forms
Follicular Carcinoma
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Capsular invasion)
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MEDULLARY CARCINOMA:
Arise from C cells CALCITONIN, CEA,
serotonin, VIP

80% Sporadic , or familial MEN Syndrome

Composed of polygonal or spindle cells ,

usually with demonstrable AMYLOID in the
stroma

Calcitonin demonstrated in tumor cells

 Level of calcitonin in serum may be useful
for follow up

Family members may show C cell

hyperplasia , Calcitonin, & RET mutation
( Marker for early diagnosis)

Metastases by blood stream

Prognosis intermediate , worse in MEN. 2B

Medullary CA with amyloid
Congo red for amyloid
ANAPLASTIC CARCINOMA :
Elderly patients with multinodular goitre
in 50%

Foci of papillary or follicular CA may be

present in 20%- 30% , probable
dedifferentiation process

Markedly infiltrative tumor , invading the

neck pressure on vital structures

Rapid progression, death within 1 year

 Morphology : Composed of
pleomorphic giant cells, spindle cells or
small cell anaplastic varients, which
may be confused with lymphoma

Radiosensitive tumor , no surgery

P53 mutation identified , consistent

with tumor progression
 PARATHYROID GLAND

Derived from the third and fourth pharyngeal pouches.

90% of people have four glands.
Location: mostly close to the upper or lower poles of the
thyroid.
Can be found anywhere along the line of descent of the
pharyngeal pouches.
There are two types of cells with intervening fat :
- Chief & Oxyphil cells
Secretion of PTH is controlled by level of free calcium
 Hyperparathyroidism : Primary OR Secondary
Primary Hyperparathyroidism:
Commonest cause of asymptomatic hypercalcemia
Female:Male ratio = 2-3 : 1.
Causes : Adenoma 75%-80%
Hyperplasia 10-15%
Carcinoma < 5%
Majority of adenomas are sporadic
5% familial associated with MEN-1 or MEN-2A
Genetic abnormalities :
PRAD 1 on chromosome 11 q cell cycle
control cyclin D1 overexpression(10%-20%)
MEN 1 on 11q13 is a cancer suppressor gene
- Germ line mutation in MEN-1 syndrome
loss of function cell proliferation
- *20% - 30% of sporadic cases may also show
mutation of MEN1
*Either of above may cause tumor or hyperplasia
 Biochemical findings :
PTH , Ca , phosphate ,alkaline
phosphatase

In other causes of hypercalcemia, PTH

is
Gland morphology in Hyperparathyroidism
Adenomas :
Usually single , rarely multiple
Well circumscribed, encapsulated
nodule (0.5-5g.)
The cells are polygonal, uniform chief
cells, few oxyphil cells. Adipose tissue is
minimal in the tumor
Compressed surrounding parathyroid
tissue in periphery, other glands normal
or atrophic .
 Hyperplasia :

Enlargement of all 4 glands.

Microscopically chief cell hyperplasia, or
clear cell, usually, in a nodular or diffuse
pattern.

Note : Diagnosis of adenoma versus

hyperplasia may depend on the size of
the other glands
Parathyroid carcinoma :

Larger than adenoma (5-10g)

Very adherent to surrounding tissue.
Pleomorphism & mitoses not reliable
criteria for malignancy
Most reliable criteria for malignancy
are :
* Invasion
**Metastases
Morphology in other organs:
Skeletal system:
Bone resorption by osteoclasts, with fibrosis,
cysts formation and hemorrhage Osteitis
Fibrosa Cystica
Collections of osteoclasts form Brown
Tumors
Chondrocalcinosis and pseudogout may occur.

Renal system:
Ca. Stones. & Nephrocalcinosis.

Metastatic calcification in other organs:

Blood vessels & myocardium , Stomach, Lung
etc
Hyperparathyroidism, clinical picture

50% of patients are asymptomatic.

Patients show Ca & PARATHORMONE levels in
serum
Symptoms and signs of hypercalcemia:
Musculoskeletal, Gastrointestinal tract, Urinary
and CNS symptoms
Commonest cause of silent hypercalcemia .
In the majority of symptomatic hypercalcemia
commonest cause is wide spread metastases to bone
Painful Bones, Renal Stones, Abdominal Groans & Psychic Moans
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Secondary Hyperparathyroidism
:
Occur in any condition associated with chronic
hypocalcemia, mostly chronic renal failure.

Glands are hyperplastic

Renal failure phosphate excretion

increased serum phosphate, CaPTH
Tertiary Hyperparathyroidism

Extreme activity of the parathyroid

autonomous function & development
of adenoma (needs surgery)
Hypoparathyroidism :
Causes:
Damage to the gland or its vessels
during
thyroid surgery.
Idiopathic, autoimmune disease.
Pseudohypoparathyroidism, tissue
resistance to PTH
Clinical features:
-Tetany, convulsion, neuromuscular
irritability, cardiac arrhythmias
ENDOCRINE PANCREAS
 Diseases mainly include :

Diabetes
Islet Cell Tumors
DIABETES
DIABETES :

Chronic disorder in which there is

abnormal metabolism, of carbohydrate, fat
& protein , characterized by either relative
or absolute insulin deficiency, resulting in
hyperglycemia.
Most important stimulus that triggers
insulin synthesis from cells is GLUCOSE
Other agents stimulate insulin release
Level of insulin is assessed by the level of
C - peptide
 Diagnosis :

1- Random glucose 200g / dL +

symptoms
2- Fasting glucose of 126 / dL on more
than one occasion
3- Abnormal OGTT when glucose level is
more than 200g / dL 2hrs. after standard
glucose load of 75 g.
Classification :
Causes could be Primary in the pancreas OR
secondary to other disease conditions

Primary diabetes is classified into :

A- Type 1
B- Type 2
C- Genetic & Miscellaneous causes
Whatever the type, complications are the
same
Type 1 :-
Absolute deficiency of insulin due to
cell destruction ( 10%)
90% of cells lost before metabolic
changes appear
Age 20 yrs but may be latent
Normal or decreased weight
Ketoacidosis is common
Type 2 :

Due to a combination of peripheral

resistance to insulin action &
inadequate secretory response by the
pancreatic cells
Commoner ( 80 - 90% )
Insulin normal (relative insulin
deficiency)
Patient is overweight
Rare ketoacidosis
Type 3 : Miscellaneous causes
Genetic defects :
cell function
e.g. Maturity Onset Diabetes of the Young
( MODY)caused by a variety of
mutations

Genetic defects of insulin processing or

action
e.g. Insulin gene or Insulin receptor
mutations
Secondary Miscellaneous Causes :

Diseases of exocrine pancreas e.g.

chronic pancreatitis
Endocrinopathies e.g. Cushings
Syndrome,
Acromegally
Infections e.g. CMV
Drugs e.g. glucocorticoids
Gestational diabetes
Other genetic syndromes associated
PATHOGENESIS
Pathogenesis of Type 1
Diabetes :
1- Genetic susceptibility
2- Autoimmunity
3- Environmental factors

It is a combination of autoimmunity &

environmental insult in a person with a
known genetic susceptibility leading to
destruction of cells
1- Genetic susceptibility
Principal susceptibility genes located in
region of MHC class II on chromosome
6p21
90% Associated with HLA- DR3,or HLA-
DR4, or both
Racial predisposition, (Caucasians) but
majority have no family history
6- 20% familial ,< 40% in identical twins
Second susceptibility gene encodes a T cell
inhibitory receptor (CTLA-4) interfering
with normal T cell function
2- Autoimmunity -

Presence of CD 8+ & CD 4+ in islet cells

Insulinitis
Presence of islet cell antibodies ( insulin
& GAD) in 80% of patients & in relatives
several months or years before onset
Antibodies are highly selective against
cells
Relatives at risk have similar AB years
before onset
3- Environmental factors
An environmental insult may damage
cells
rendering them antigenic.

Viruses : measles , coxsackie ,

rubella
Chemicals
Cows milk
Pathogenesis of Type 2 diabetes
:

1- Genetic factors
2- Insulin resistance & obesity
3 - cell secretion dysfunction
1- Genetic factors :

Genetic factors are more important than in

type 1 diabetes, but this is multifactorial
50% - 90% in identical twins
risk by 20%-40% in first degree relatives
No association with HLA & no autoimmune
basis
Point mutation in insulin receptor identified
affecting signaling pathway but rare ( 1-5%)
2 Insulin resistance :

Decrease ability of peripheral tissue to

respond to insulin
Early : insulin resistance insulin
secretion due to compensatory of cell
mass
Later : relative insulin & cell mass to
20-50%
MAIN FACTOR IN INSULIN RESISTANCE IS
OBESITY
Explanation :

Adipocytokines :

Resistin obesity Insulin resistance

Leptin & Adiponectin contribute to
insulin sensitivity but are in obesity
resistance
PPAR is a nuclear receptor that
regulates level of adipocytokines
FFA in tissues (lipotoxic effect)
insulin resistance
 3- cell Dysfunction :

Defective glucose recognition due to

intracellular levels of a mitochondrial protein
( UCP2) in cells

Amylin :

A protein normally produced by cells secreted

with insulin in response to food ingestion
Amylin accumulates outside cells, forming
amyloid like deposits & may impair cell
glucose sensing.
Seen in up to 90% of cases of Type II diabetes
Pathogenesis of complications :
1- Nonenzymatic glycosylation of proteins
Glucose + Free amino acids
Later Irreversible combination
Advanced Glycosylation End products
=AGES
Measured by level of glycosylated Hb
( HbA1c)
AGES inactivate proteins & cross link with
more proteins, deposited in vessels,
renal glomeruli, ..etc
Effects :
Induce cytokine production, GF :
vascular permeability
procoaggulant activity
fibroblasts & SM in ECM

Complications in blood vessels, kidney,

nervous system .etc
Complications are proportional to the
degree
of hyperglycemia of whatever type
2- The Polyol Pathway

Persistent hyperglycemia facilitates

entry of glucose & its accumulation
into some cells & metabolized into
SORBITOL (a polyol) &
FRUCTOSE
Creation of osmotic gradient Influx
of fluid + Toxic
lens, retina, peripheral nerves,
kidneyetc
3- Activation of Protein Kinase C :

Activation of signal transduction

Leads to production of pro-angiogenic
factors (VEGF)
Important in retinal neovascularization
Production of pro-fibrogenic factors
ECM & BM thickening
COMPLICATIONS
Pathology in the Pancreas
i -Type I :
- Leukocytic infiltration of islets ( T cells)
Insulinitis with progressive depletion of
cells.
- Later small indistinct or absent islets.
ii - Type II :
- Ill defined reduction in islet cell mass
- Fibrous tissue accumulation in some islets
- Amyloid deposition in islets
Newborn of diabetic mother : islet cell
hyperplasia
COMPLICATIONS
1- Atherosclerosis :

- Cardiovascular
- CNS complications
- Peripheral circulation

2- Diabetic microangiopathy
- Hyaline arteriolosclerosis , exaggerated in
hypertension
- Diffuse thickening in capillaries of skin, retina
peripheral nerves, renal medulla Leaky
vessels nephropathy, retinopathy, neuropathy
3- Diabetic nephropathy

I - Glomerular lesions-
- Capillary BM thickening
- Nodular glomerulosclerosis 15% -30%
( Kimmelstiel - Wilson lesion)
- Diffuse mesangial sclerosis

II - Renal vascular lesions

- Renal atherosclerosis
- Hyaline arteriolosclerosis
Kimmelstiel- Wilson lesion
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III Pyelonephritis

- Acute & chronic interstitial

inflammation
- Necrotizing papillitis / papillary
necrosis
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4- Ocular complications :

I - Retinopathy :
- Nonproliferative : hemorrhage, exudate,
microaneurysm, edema
- Proliferative : Neovascularization, fibrosis,
retinal detachment
II - Cataract formation
III - Glaucoma
5- Diabetic neuropathy
I - Peripheral sensory & autonomic nerve dysfunction
( microangiopathy & demyelination )
II - Neuronal degeneration
III - Degenerative spinal cord lesions

6- Recurrent infections : Bacterial & mycotic

 Clinical Features in Diabetes :

Type 1 :
Age < 20 , but some are latent (LADA)
May present with metabolic acidosis,
weight loss, dehydration,& electrolyte
imbalance.
Polyuria , Polydipsia, Polyphagia ( 3Ps)

Findings : - Hyperglycemia
- Glucosuria Ketonuria
Type 2 :

Age > 40yrs., often present incidentally

Patients may have the 3 Ps symptoms
of complications
Hyperosmolar nonketotic coma caused
by dehydration due to uncompensated
hyperglycemic diuresis.
No keto acidosis
Increased susceptibility to infections
ISLET CELL TUMORS
Islet Cells & Secretions :

cells insulin
cells glucagon
cells somatostatin
Pancreatic polypeptide ( PP) VIP
 Islet Cell Tumors of Pancreas :
Include insulinomas, gastrinomas,
glucagonomas.etc
Less frequent than pancreatic CA
Maybe functioning or nonfunctioning
Tumors 2 cm. diameter likely to be
benign
Associated clinical syndromes :
1- Hyperinsulinism (Insulinomas)
2- Zollinger - Ellison Syndrome
( Gastrinomas)
3- Multiple endocrine neoplasia (MEN)
 Insulinoma :
Commonest type
Hypoglycemia 50 mg./dl.
Attack precipitated by fasting or exercise, relieved by
eating or glucose administration
Lab. : serum glucose , serum insulin
Most tumors in pancreas but can be ectopic
Most tumors solitary ( < 2cm.), can be multiple
Majority are benign, 10% can be malignant
Histologically difficult to diagnose malignancy
 Gastrinomas :

More in middle aged females

Located in pancreas , duodenum or peripancreatic
tissue
Single or multiple, or associated with other tumors
> 50% locally invasive or have metastasized at
diagnosis
Present with Zollinger- Ellison Syndrome
Zollinger - Ellison Syndrome :
Peptic ulcer disease
Ulcer features :
Multiple ulcers
Unusual locations specially jejunum
Intractable
Gastrin hypersecretion
Diarrhea in > 50% & may be the presenting
symptom
Rare tumors :

- Cell tumors : Middle aged women

Glucagon secretion , mild diabetes,
skin rash, anemia
- Cell tumors : Somatostatin secretion

Diabetes, malabsorption, GB stones
VIPomas : VIP secretion
Watery diarrhea, hypokalemia,
achlorhydria
ADRENAL GLAND
 ADRENAL GLAND
Weight of normal gland is 4 gm.
Adrenal Cortex - Derived from mesoderm & composed
of
1- Zona glomerulosamineralocorticoids (aldosteron)
2- Zona fasciculata glucocorticoids ( cortisol )
3- Zona reticularis estrogens & androgens

Diseases are those of hyperfunction & hypofunction

& tumors
Adrenal Medulla
Derived from neural crest & is part of sympathetic
system.
Composed of Chromaffin cells secreting catecholamines
Diseases are mainly tumors
Congenital Anomalies

Incidental finding of adrenal tissue in the

inguinoscrotal path , mainly in males
Fusion of adrenals
Congenital adrenal hyperplasia
Ectopic tissue in adrenal : liver, thyroid & ovarian
tissue
 ADRENOCORTICAL HYPERFUNCTION :

There are 3 syndromes associated with hyperfunction:

1- Cushings Syndrome & Cushings Disease

2- Conns Syndrome & Hyperaldosteronism

3- Adrenogenital Syndrome
CUSHINGSyndrome

Elevation of cortisol level , which occurs in one of four

ways
A- Endogenous causes :
i- ACTH*secreting pituitary microadenoma, few
macroadenomas, OR hyperplasia
(CUSHINGs DISEASE)
ii-Adrenal tumor or hyperplasia
iii- Paraneoplastic syndrome
B- Exogenous cause :
Steroid Therapy

Tests used are :

Level cortisol in plasma,or excretion of 17hydroxy
steroids in urine, diurnal pattern , level of ACTH, &
Dexamethasone Suppression test.
Morphology of adrenals in Cushings Syndrome :
This depends on the cause :
1- Exogenous increase glucocorticoids ACTH
Bilateral atrophy of adrenals
2 -Endogenous hypercorticolism:
a- Presence of adrenal adenoma or carcinoma,
with atrophy of adjacent & contralateral adrenal
b- Secondary to ACTH secreting adenoma
bilateral diffuse or nodular hyperplasia
c- Primary adrenal nodular hyperplasia
The pituitary in all forms of Cushings syndrome shows
Alteration in ACTH producing cells :

Granular basophilic cells show lighter homogenized

cytoplasm due to accumulation of intermediate keratin
filaments in cytoplasm , called :
Crookes Hyaline Change
Clinical features of Cushings syndrome :

Main symptoms include :

Central obesity/ moon face
Hypertension
Hirsutism/ menstrual disturbances
Diabetes
Osteoporosis
Increased risk of infections
Pigmentation of skin
HYPERALDOSTERONISM :

Excess level of aldosterone cause sodium retension,

potassium excretion, resulting in hypertension &
hypokalemia.

Type could be primary OR secondary

A- Primary : Conn Syndrome
Caused by Adenoma (80%) F:M is 2:1
Single or multiple
Or primary adrenal hyperplasia ( 15% ) ,
Carcinoma is rare

Adjacent adrenal cortex is NOT atrophic

There is aldosteron Na retention & K excretion
BP , Hypokalemia , RENIN
Correctable cause of HYPERTENSION
B- Secondary :
Due to decreased renal perfusion,
activation of the renin - angiotensin system
aldosteron

Differentiate from primary by RENIN

VIRILIZING Syndromes :

Could be caused by - primary gonadal disorders

- Adrenocortical Neoplasms
- Congenital adrenal hyperplasia
Neoplasms can occur at any age, frequently malignant
Congenital adrenal hyperplasia is caused by an enzyme
defect in cortisol synthesis (21 hydroxylase)
NO CORTISOLACTH androgenic steroids
Virilization , precocious puberty, ambiguous genitalia
Patients have risk for acute adrenocortical insufficiency
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MORPHOLOGY in ALL ADRENAL TUMORS:
Encapsulated , usually yellow
Size variable 1-2 cm. ( 30gms.)Up to large tumors
Most incidental nonfunctioning tumors, may be
functioning
Malignant tumors with necrosis, hemorrhage ( 300gms)
Usually larger , more aggressive in adults
Both may show same appearance of uniform or slightly
pleomorphic cells ,may be eosinophilic or clear
Local invasion ,& the presence of metastases
differentiate benign from malignant tumors
Cortical Adenoma
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Adrenocortical carcinoma
ADRENOCORTICAL INSUFFICIENCY :
May be primary adrenal or secondary to destruction of the
pituitary as in SHEEHANs syndrome.etc
Primary in adrenal may be :
A- Acute :
1- Massive adrenal hemorrhage as in anticoaggulant
therapy, DIC, sepsis by N.meningitidis,pseudomonas
( Waterhouse- Friderichsen syndrome)
2- Sudden withdrawal of steroid therapy
3- Stress in a pt.with underlying chronic insufficiency
Adrenal hemorrhage
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Adrenal insufficiency (continued )
B- Chronic :( Addisons disease )
Progressive destruction of the adrenal by :
1- Autoimmune Disorder: 75-90 % , may be sporadic
or familial, linked to HLA-B8 , DR3, HLA-DQ5
Often multisystem involvement

2- Infections e.g. Tuberculosis , fungii ( AIDS)

3- Metastatic tumors destroying adrenal e.g. lung,

breast , others
 Morphology & Clinical features in Chronic Adrenal
Insufficiency :
Morphology depends on cause :

Autoimmune :
Irregular small glands, cortex infiltrated by lymphocytes,
medulla normal.
T.B. Caseating Granuloma
Metastatic disease Type of primary tumor
Secondary to pituitary cause : the adrenal is shrunken
 Clinical features :

Weight loss, hypotension, hypoglycemia,

pigmentation.
There is Hyperkalemia & Hyponatremia due to
mineralocorticoids
THE ADRENAL MEDULLA :

Composed of CHROMAFFIN CELLS & nerve endings

Secretetes cholamines in response to sympathetic
stimulation
Also present in extra-adrenal sites

Pathology includes tumors :

A- Pheochromocytoma
B- Neuroblastoma
PHEOCHROMOCYTOMA :
Secretes catecholamines VMA
Sometimes described as The 10% Tumor because :
* 10% bilateral
* 10% extra adrenal ( Paraganglioma)
* 10% familial, maybe part of MEN syndrome
* 10% Malignant
Usually well circumscribed,small to large in size,maybe
pleomorphic. Malignancy confirmed by METASTASES
Clinically sustained or paroxysmal attacks of BP
CORRECTABLE cause of HYPERTENSION
Pheochromocytoma
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NEUROBLASTOMA :
Commonest extracranial solid tumor of childhood
Usually adrenal but maybe extra-adrenal
Familial or sporadic
Associated with deletion of short arm of chromosome 1
90% associated with catecholamine secretion
VMA excreted in 24 hr. urine helpful in diagnosis.
Morphologically it is composed of small round blue cells
which may differentiate to ganglion cells
Spread to adjacent organs, lymph nodes, renal vein.
Prognosis : STAGE , AGE , N myc amplification
MULTIGLANDULAR SYNDROMES
 POLYGLANDULAR SYNDROME :
Autoimmune disease
Familial or sporadic
Isolated involvement of adrenals
Multiorgan involvement
Type I : autosomal recessive associated with mutation
on immune regulator gene on Chr. 21
Type II : multifactorial, linked to
HLA-B8 , HLA-DR3 , HLA-DQ5
Include Hashimotos thyroiditis,adrenalitis, diabetes type I,
pernicious anemia
 MEN SYNDROME :

Inherited syndrome with multiple endocrine tumors &

or hyperplasia of component cells
Tumors occur at younger age
Often preceded by asymptomatic OR symptomatic
hyperplasia in involved organ
Tumors may be multifocal in the same organ
Often more aggressive than the same tumor without
MEN syndrome
Types of MEN syndromes :

Type MEN 1 : ( 3 Ps)

Autosomal dominant
Involves suppressor gene on 11q.13
Parathyroid : multiglandular parathyroid
hyperplasia (95%]
Pancreas: aggressive,multifocal functional
gastrinomas & insulinomas
Pituitary: Prolactinoma GH
 Type MEN 2 :
Autosomal dominant Proto-oncogen mutation :
RET/10q 11
MEN 2 A :
Medullary carcinoma of thyroid + C cell hyperplasia
Pheochromocytoma (50%)
Parathyroid hyperplasia
MEN 2 B :
As above but no parathyroid hyperplasia
Extra endocrine manifestations :
e.g. mucosal neurofibromas