Transcript PATHOLOGY OF THE ENDOCRINE SYSTEM

PATHOLOGY OF ENDOCRINE
SYSTEM
2009
Dr. Huda M Zahawi, FRC.Path
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 )
N.B. 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
2- ADH
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 ( α 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
GTPase
• Mutations in α 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
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:
Nelson’s 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 α subunit, β- FSH & β-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.
SHEEHAN’S 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 Rathke’s 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 hypothalamus…etc.
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- Hashimoto’s 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 ( Hashimoto’s )
thyroiditis
2- Subacute granulomatous ( de Quervain)
thyroiditis
3- Subacute lymphocytic thyroiditis
4- Riedel thyroiditis
5- Palpation thyroiditis
HASHIMOTO’s 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- γ)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 Hashimoto’s thyroiditis
without Hurthle cell metaplasia
• Reidel’s Thyroiditis –
Dense fibrosis without prominent inflammation
? Considered as fibromatosis rather than thyroiditis
GRAVE’S 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 GRAVE’S 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,
Addison’s 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 & cabbages…etc
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.
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
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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 ½ of cases OR
– PAX8- PPAR γ 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,  CaPTH
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 β 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 β 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 β cells
• Commoner ( 80 - 90% )
• Insulin normal (relative insulin deficiency)
• Patient is overweight
• Rare ketoacidosis
Type 3 : Miscellaneous causes
• Genetic defects :
– β 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. Cushing’s Syndrome,
Acromegally
• Infections e.g. CMV
• Drugs e.g. glucocorticoids
• Gestational diabetes
• Other genetic syndromes associated with
diabetes
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 β cells
1- Genetic susceptibility
– Principal susceptibility genes located in
region of MHC class II on chromosome 6p21
– 90% Associated with HLA- DR3,or HLADR4, 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 β cells
• Relatives at risk have similar AB years before
onset
• 10% - 20% other autoimmune disease
3- Environmental factors
An environmental insult may damage β cells
rendering them antigenic.
•
•
•
Viruses : measles , coxsackie , rubella
Chemicals
Cow’s 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 γ 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 β 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, kidney…etc
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 ( 3P’s)
• Findings :
- Hyperglycemia
- Glucosuria ± Ketonuria
- Electrolyte imbalance
Type 2 :
• Age > 40yrs., often present incidentally
• Patients may have the 3 P’s  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 :
•
•
•
•
β cells  insulin
α cells  glucagon
δ 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 :
• α- Cell tumors : Middle aged women
Glucagon secretion , mild diabetes, skin
rash, anemia
• δ- 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 glomerulosamineralocorticoids (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- Cushing’s Syndrome & Cushing’s Disease
2- Conn’s Syndrome & Hyperaldosteronism
3- Adrenogenital Syndrome
CUSHING’Syndrome
• Elevation of cortisol level , which occurs in one of four
ways
A- Endogenous causes :
i- ACTH*secreting pituitary microadenoma, few
macroadenomas, OR hyperplasia
(CUSHING’s 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 Cushing’s 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 Cushing’s syndrome shows
Alteration in ACTH producing cells :
• Granular basophilic cells show lighter homogenized
cytoplasm due to accumulation of intermediate keratin
filaments in cytoplasm , called :
•
Crooke’s Hyaline Change
Clinical features of Cushing’s 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 CORTISOLACTH 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 SHEEHAN’s 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 :( Addison’s 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 Hashimoto’s 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