OLEH :

Dr. Jusuf Fantoni,

SpPA (K), MSc
Path
SISTEM ENDOKRIN = SISTEM
REGULAR TERPENTING1

Melalui hormon bekerja pada:

Metabolisme
Pertumbuhan
Reproduksi
Aktifitas Mental
Adaptasi
Aktifas fungsional semua
organ
 JENIS KELAINAN
ENDOKRIN 2:

A. Hiperfungsi Kelenjar Endokrin

B. Hipofungsi Kelenjar Endokrin

C. Disfungsi Kelenjar Endokrin

PENYEBAB KELAINAN ENDOKRIN :3
Trauma mental
Nekrosis
Tumor
Proses Radang
Infeksi Bakteri dan Virus
Kuatumor
Gangguan dari kulasi daerah
setempat
Kelainan tractus gastro-intestinal
Radiasi
Kelainan Kromosom dan Genetik
THE ENDOCRINE SYSTEM IS
DIVIDED INTO :4
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 :5

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

N.B. Correlation of clinical picture,

hormonal assays, biochemical
findings, together with pathological
picture are of extreme importance
in most conditions.
 PITUITARY GLAND6
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 :7
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
2-ADH
 HYPERPITUITARISM & PITUITARY
ADENOMA8

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
 HYPERPIRITARY :OLEH ADENOMA
DARI SEL ENDOKRIN9

1. Eosinophilic adenoma
Dari sel acidophilic
adenohypophysis (STH)
2. Basophilic adenoma dari sel
Basofilik adenoa hypophysis (ACTH)
PATHOGENESIS OF PITUITARY ADENOMAS :10
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:

Mutations 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 :11

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:12

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 :16

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 ADENOMAS19

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 :26
Galactorrhea
Amenorrhea
Decrease libido
Infertility
2 - Growth hormone secreting
adenoma :27
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
3 - CORTICOTROPH CELL
ADENOMA28
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 ONLY29

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 : 31

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 32for 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 :36

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:37

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.
 HIPERFUNSI NEUROHYPOPHYSIS

MERANGSANG
LAKTASI

MEMULAI DAN
OXYTOCI MENGUATKAN
N KONTRAKSI UTERUS

MERUSAK INGATAN
(ANURESTIC
HORMONE)
THYROID GLAND
 Development from evagination of
pharyngeal tissue into neck 41
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:42

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 43

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 :46

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 :48

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,accumulatioQn of
mucopolysaccharides in subcutaneous
tissue
 THYROIDITIS : 50
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 51

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 : 52

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-
 MORPHOLOGY: 53

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 : 56

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) 57

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 : 59

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 : 60

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 :61

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 :62

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 :63

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 :65
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
 DIFFUSE NONTOXIC &
MULTINODULAR GOITRE

GOITER = Enlargement of thyroid67

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 : 68

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.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM)
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 GENERAL RULES OF NODULES IN THE THYROID :
72

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 :74

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 : 75

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
Adenoma with intact capsule 2005 Elsevier
 CARCINOMAS OF THYROID : 78

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 : 79

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 : 80

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
2- Environmental Factors : 82
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 : 84
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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2005 Elsevier
 DIAGNOSIS BASED ON NUCLEAR
FEATURES 86

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
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of Papillary CA (nuclear changes) 2005 Elsevier

Psammoma body in Papillary CA
 FOLLICULAR CARCINOMA :90
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
 MEDULLARY CARCINOMA:92

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
 ANAPLASTIC CARCINOMA :95

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 97

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
 HYPOPARATHYROIDISM : 107

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 with
diabetes
PATHOGENESI
S
 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
10% - 20% other autoimmune disease
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
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
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, kidney
etc
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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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
- Electrolyte imbalance
 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
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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
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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
MULTIGLANDULA
R SYNDROMES
POLYGLANDULAR SYNDROME :
Autoimmune disease
Familial or sporadic
Isolatedinvolvement 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
Thank You