ENDOCRINE SYSTEM

Nila Kurniasari
Dept Patologi Anatomi
FK UNAIR
 Endocrine Organs
• Purely endocrine organs
– Pituitary gland
– Pineal gland
– Thyroid gland
– Parathyroid glands
– Adrenal: 2 glands
• Cortex
• Medulla
• Endocrine cells in other
organs
– Pancreas
– Thymus
– Gonads
– Hypothalamus
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 Sits in hypophyseal fossa: depression in sella turcica of
sphenoid bone
The Pituitary

Two divisions: 1. TSH

2. ACTH
3. FSH
• Anterior pituitary 4. LH_
(adenohypophysis) 5. GH
6. PRL

_________________________________________________________________

• Posterior pituitary
(neurohypophysis) 7. ADH (antidiuretic hormone), or vasopressin
8. Oxytocin

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Symptoms and signs of pituitary
disease can be grouped as follows:

• Hyperpituitarism-related effects --> ec excessive

secretion of trophic hormones --> most often results from
an anterior pituitary adenoma, etc
• Hypopituitarism-related effects: caused by deficiency of
trophic hormones and results from a variety of
destructive processes
• Local mass effects: abnormalities of the sella turcica,
including sellar expansion, bony erosion, and disruption
of the diaphragma sellae.
optic nerves and chiasm close to the sella,--> visual field
abnormalities.

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Hyperpituitarism

▪ Adenoma
▪ Hyperplasia
▪ Carcinoma
▪ Hypothalamus disorder

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Pituitary Adenoma

• Classified on the basis of hormone(s)

produced by the neoplastic cells -->
immunohistochemistry
• functional vs nonfunctioning
• sporadic/ non familial (most), inherited
(5%)
• microadenoma(< 1 cm), macroadenoma >
1cm

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Classification of Pituitary Adenoma

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Pituitary Adenoma Clinical feature

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Pituitary Adenoma macroscopic

well-circumscribed, soft lesion that may, in the case of smaller tumors, be confined by the sella
turcica. Larger lesions may compress the optic chiasm and adjacent structures

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Pituitary Adenoma microscopic

Pituitary adenomas are composed of relatively

uniform,polygonal cells arrayed in sheets, cords, or papillae.
The nuclei of the neoplastic cells may be uniform or 10
pleomorphic. Mitotic activity usually is scanty
HYPOPITUITARISM

• Underproduction of pituitary
gland hormones.
• Hypopituitarism is noted
clinically if there is a loss of 75%
or more of the gland.

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Causes of hypopituitarism

• Null cell pituitary adenoma

• Ischemic injury: in Sheehan
syndrome
• Pituitary apoplexy: sudden
hemorrhage
• Empty sella syndrom: herniation
• Others : surgery, radiation,
inflammatory reactions,DIC, and
sickle cell anemia 12
Infarct of pituitary gland. This pituitary gland is almost
entirely infarcted. Only a thin rim of viable cells remains (arrow).
Pituitary infarcts occur during pregnancy (Sheehan syndrome), 13
and can occur as a result of cerebral edema.
PATHOLOGY OF THE POSTERIOR
PITUITARY GLAND
1.SYNDROME OF INAPPROPRIATE
ANTIDIURETIC HORMONE (SIADH)
caused by hyperfunctioning of the posterior
pituitary gland 🡪 (ADH)
🡪 water retention and hyponatremia.
causes: ectopic ADH (secreted by small cell lung
carcinoma), non neoplastic lung disease (TB,
pneumonia), CNS disorder, injury
symptoms: headache, anorexia, vomiting,
confusion (sodium level 115–120 mEq/L), and
stupor; coma and seizures (sodium level 110
mEq/L).

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PATHOLOGY OF THE POSTERIOR
PITUITARY GLAND
2. DIABETES INSIPIDUS
caused by hypofunctioning of the
posterior pituitary gland 🡪 ADH
types of diabetes insipidus
• Central diabetes insipidus: decreased
production of ADH.
• Nephrogenic insipidus: decreased renal
responsiveness to ADH.
symptoms: polyuria and polydipsia.

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The Thyroid Gland

• Anterior neck on trachea

just inferior to larynx
• Two lateral lobes and an
isthmus
• Produces two hormones
– Thyroid hormone:
tyrosine based with 3 or 4
iodine molecules
• T4 (thyroxine) and T3
– Calcitonin involved with
calcium and phosphorus
metabolism

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• Thyroid is composed of spherical follicles
– Follicle cells: produce thyroglobulin, the
precursor of thryoid hormone (thyroxin)
– Colloid lumen is of thyroglobulin
– Parafollicular “C” cells: produce calcitonin

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HYPERTHYROIDISM

• the basal metabolic rate and the organ’s

sensitivity to catecholamines.
• Laboratory findings of primary
hyperthyroidism: TSH and T4;
occasionally, patients will have only an
T3.
• Causes of primary hyperthyroidism:
Graves disease and toxic goiter
(common)

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HYPERTHYROIDISM
• Signs and symptoms
■ constitutional symptomps: heat
intolerance, sweating, and warm, flushed
skin,weight loss associated with
increased appetite.
■ cardiac: palpitations, tachycardia
■ GI: hypermotility,malabsorption, diarrhea.
■ Neuromuscular: nervousness,tremor, and
irritability. 50% develop proximal muscle
weakness (thyroid myopathy).

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HYPERTHYROIDISM
■ Ocular : a wide, staring gaze and lid lag are
present because of sympathetic overstimulation of
the levator palpebrae superioris

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 HYPERTHYROIDISM
■Thyroid storm is : the abrupt onset of
severe hyperthyroidism. occurs in Graves disease,
Thyroid storm 🡪medical emergency 🡪 die of cardiac
arrhythmias.

■Apathetic hyperthyroidism : thyrotoxicosis occurring

in elderly persons, in younger patients :blunted.

•The diagnosis : based on clinical features and

laboratory data.
• A low TSH value usually is associated with
increased levels of free T4.
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HYPOTHYROIDISM

• caused by any structural or functional derangement that

interferes with the production of adequate levels of
thyroid hormone.

• primer or secunder

• Worldwide, the most common cause of hypothyroidism is

dietary deficiency of iodine while in most developed
nations, autoimmune causes predominate.

• The clinical manifestations of hypothyroidism include

cretinism and myxedema.

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Cretinism
• Results from thyroid hormone
insufficiency in infancy

• Protuberant abdomen
• Short Stature
• Infertility
• Neurological
impairment
• Constant Fatigue
• Obesity
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Myxedema
The term myxedema is applied to hypothyroidism developing in the
older child or adult.
• slowing of physical and
mental activity.
• generalized fatigue
• apathy
• listless, cold intolerant,
overweight.
• constipation and decreased
sweating.
• The skin is cool and pale
because of decreased
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blood flow
THYROIDITIS

• inflammation of the thyroid gland :

(1) Hashimoto thyroiditis (or chronic
lymphocytic thyroiditis);
(2) Granulomatous (de Quervain)
thyroiditis;
(3) Subacute lymphocytic thyroiditis.

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Chronic Lymphocytic (Hashimoto) Thyroiditis

• Pathogenesis: Inflammatory autoimmune

destruction of the thyroid gland.

• Epidemiology: occurs commonly between

45 and 65 years of age; female to male
ratio is 10:1 to 20:1.

• associated with both Down and Turner

syndromes, and is the most common
cause of hypothyroidism and goiter in the
United States.
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Chronic Lymphocytic (Hashimoto)
Thyroiditis
• Gross: Pale, vaguely nodular thyroid
gland.
• Microscopic: Lymphocytic infiltrate, plasma
cell, usually with lymphoid follicle
formation, and oncocytic change in
follicular epithelium.
• Clinical presentation:Insidious onset of
hypothyroidism due to gradual loss of
thyroid function.
• Diagnosis : High TSH; anti-thyroid
peroxidase and anti-thyroglobulin
antibodies (90% of cases).
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Chronic Lymphocytic (Hashimoto)
Thyroiditis

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DE QUERVAIN OR
GRANULOMATOUS THYROIDITIS
• Epidemiology: 40 and 50 years of age;
female to male ratio is 4:1.
• Pathogenesis: Often follows a viral infection
• Symptoms: Neck pain, fever.

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SUBACUTE (DE QUERVAIN OR
GRANULOMATOUS)THYROIDITIS
• Signs
-Most characteristic is a markedly tender
thyroid gland upon palpation.
-Early transient hyperthyroidism (2 to 6
weeks) is followed by a hypothyroid phase.
-Most patients resume normal thyroid
function within 6-8 weeks.

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DE QUERVAIN OR
GRANULOMATOUS THYROIDITIS
• Gross:
The gland may be unilaterally or
bilaterally enlarged and firm, 
with an intact capsule that may 
adhere to surrounding structures.
• Microscopic morphology:   aggregates
of  lymphocytes,
activated macrophages, plasma cells
and multinucleated giant cells.

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 https://webpath.med.utah.edu/ENDOHTML/ENDO019.html

This is subacute granulomatous thyroiditis (DeQuervain disease),. Note the

presence of large foreign body giant cells with inflammatory destruction of
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thyroid follicles.
 GRAVE DISEASE

Triad:
1. Hyperthyroidism due to diffuse,
hyperfunctional enlargement of the
thyroid
2. Infiltrative ophthalmopathy with
resultant exophthalmos
3. Localized, infiltrative
dermopathy, sometimes called
pretibial myxedema, which is
present in a minority of patients
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Epidemiology:
o 20-40 yrs, female : male = 10 : 1
o genetic susceptibility :
polymorphisms in immunefunction
genes like CTLA4 and PTPN22 and
the HLA-DR3 allele.

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Pathogenesis

Graves disease is characterized by a breakdown in

self-tolerance to thyroid autoantigens, of which the
most important is the TSH receptor. The result is the
production of multiple autoantibodies,
including:
1. TSI = Thyroid stimulating immunoglobulin
2. TGI = Thyroid growth stimulating immunoglobulin
3. TSH binding inhibitor immunoglobulin ( antibody anti TSH
receptor )

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Diffuse / Multinodular Goiter

Medeiros-Neto G. Multinodular Goiter. [Updated 2016 Sep 26]. In: Feingold KR, Anawalt B,
Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.;37
2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK285569/
Diffuse Non Toxic ( simple ) Goiter

a. Endemic
– Pada semua usia terutama muda
– Pada daerah rendah jodium 🡪
pegunungan
– 10 % populasi (+)
– Ada faktor 🡪 goitrogen :
-calcium - lobak/radish
-kubis/cabbage
-singkong/cassava
-blumkol/cauliflower 38
b. Sporadik
– Wanita > pria
– Usia pubertas – dewasa muda
– Terdapat perubahan kelainan pada :
- transport jodium
- dehalogenase
- organification
- iodotyrosin coupling
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Morfologi : 2 stadium

1. Hiperplasi 🡪 membesar simetrik diffuse

100 – 150 gr
2. Involusi colloid 🡪 membentuk kelenjar yg
kaya colloid 🡪 colloid goiter

Klinik :
– pada anak2 🡪 hipotiroidi 🡪 cretinisme
– Pada dewasa 🡪 keluhan sedikit

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Multinodular goiter

• Dapat sporadik atau endemik

• Usia lebih tua
• Menyerupai neoplasm

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 Patogenesis

Hiperplasi
TSH 🡪 Tiroid Folikel besar
Involusi colloid
Nodul2 fibrosis Per-dara
bergabung kalsifikasi han pecah

Multinudular
goiter 42
Morfologi :

• Multilobulated sp 2.000 gr
• Asimetrik, masuk ke substernal 🡪 plunging
goiter
• Bila 1 nodul dominan 🡪 solitary nodule
(adenomatous goiter)
• Irisan warna coklat, gelatinous, fibrosis,
perdarahan, kalsifikasi, kistik
• Mikroskopis : folikel banyak colloid, epitel
pipih, atrofik/hiperplasi 43
Klinik :

• Bila besar 🡪 gangguan kosmetik

🡪 tekanan pada trachea,
2
oesophagus, vena

• Bila salah satu nodulnya hiperfungsi

🡪 Plummer Syndrome
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THYROID NEOPLASM

✔ Solitary nodules, in general, >> neoplastic

✔ Nodules in younger patients >> neoplastic
✔ Nodules in males >> neoplastic
✔ A history of radiation treatment to the head
and neck region --> increased incidence of
thyroid malignancy.
✔ Nodules that take up radioactive iodine in
imaging studies (hot nodules) >> benign

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PAPILLARY THYROID CARCINOMA

• Epidemiology: Any age, but usually

between 20 and 40 years of age.
• More than 80% of thyroid neoplasms are
diagnosed as papillary thyroid carcinoma.
• Mutations: RET proto-oncogene (10q11);
BRAF, RAS.
• Risk factors: Ionizing radiation.

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PAPILLARY THYROID CARCINOMA
• Important points
■ Papillary thyroid carcinoma has a good
prognosis, even with lymph node
metastases. At presentation, cervical lymph
node metastases are common.
■ The tumor is often multifocal.
■ Poor prognosis is associated 55 years, and
tall cell variant.

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 PAPILLARY THYROID CARCINOMA
Morphology of papillary thyroid carcinoma
■ Gross: Variable; sometimes encapsulated.
■ Microscopic: “Orphan Annie” eye / ground
glass nuclei (i.e., clear nuclei), overlapping
nuclei, nuclear grooves,
pseudo-inclusions, psammoma bodies,
and papillary architecture.

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PAPILLARY THYROID CARCINOMA

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FOLLICULAR ADENOMA AND
CARCINOMA
Epidemiology: Older patients.
• Incidence: Adenomas occur frequently;
follicular carcinomas
• account for >10% of malignant thyroid
neoplasms.

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FOLLICULAR ADENOMA AND
CARCINOMA
Mutations
■ Adenoma: TSH receptor gene GNAS1.
Mutation in TSH receptor or α-subunit of
GS leads to the activation of cAMP
pathway.
■ Carcinoma: PAX8-PPAR1 (on
t(2;3),(q13;p25)); one half of tumors have
a mutation of RAS.

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FOLLICULAR ADENOMA AND
CARCINOMA

■ Gross: adenoma: single nodule,encapsulated

carcinoma: well circumscribed or widely
invasive
■ Microscopic : Identification of capsular or
blood vessel invasion is most important to
differentiate between adenoma and carcinoma.
• Follicular carcinoma has capsular or blood
vessel invasion, while adenomas do not.
• Blood vessel invasion must be in the blood
vessels outside the neoplasm.
• Adenomas usually have thin capsules, whereas
carcinomas have thick capsules.
Follicular adenoma

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Follicular carcinoma
Parathyroid glands

• Four nodules located in

the back of the thyroid
gland
• Secreted parathyroid
hormone or
parathormone or PTH
• Action of PTH opposes
action of calcitonin
• Both hormones play a
role in calcium
metabolism

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HYPERPARATHYROIDISM

Signs and symptoms of hyperparathyroidism (due

to hypercalcemia)
• Fractures due to weakened bones.
• Kidney stones.
• Psychiatric symptoms; abdominal pain.
• Seizures.
• Constipation, muscular weakness, and
hypotonia:
High calcium levels hyperpolarize the
neuromuscular membranes -->muscle is refractory
to stimulus, resulting in weakness and
constipation.
• Electrocardiogram has short QT interval.
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PRIMARY HYPERPARATHYROIDISM
Causes
• Parathyroid adenoma (70–80% of cases)
• Hyperplasia.
• Carcinoma (rare: < 1% of cases).

Mutations: PRAD1; MEN1 (in sporadic tumors as

well).
• Important point: Adenomas are confined to a
single gland.
• If more than one gland is enlarged, the condition
is hyperplasia.

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PRIMARY HYPERPARATHYROIDISM
Complications
• Osteitis fibrosa cystica: Thinned cortex;
hemorrhage and cysts in bone, with
changes most prominent in the phalanges
and skull.
• Brown tumors: Intraosseous
accumulations of osteoclasts and giant
cells
• Nephrolithiasis.
• Lab : Elevated PTH; hypercalcemia.

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Parathyroid adenoma. The arrow indicates the border
between normal parathyroid gland (right half of image) and the
parathyroid adenoma (left half of image). Note the lack of adipose
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tissue within the adenoma. Hematoxylin and eosin, 40.
SECONDARY
HYPERPARATHYROIDISM
Causes
• Renal failure: Decreased phosphate excretion
elevates phosphate levels, which depress
calcium activity.
• Also, renal failure causes reduced synthesis of
active vitamin D.
• Vitamin D deficiency.
• Laboratory findings: Elevated PTH,
hypocalcemia, and hyperphosphatemia.

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TERTIARY HYPERPARATHYROIDISM

• Overview: Tertiary hyperparathyroidism is

secondary hyperparathyroidism that
becomes autonomous (i.e., the
parathyroid gland no longer requires the
stimulus of renal failure to undergo
hyperplasia.)

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HYPOPARATHYROIDISM

• The most common cause is iatrogenic.

• Other causes include congenital absence
(in DiGeorge syndrome) and autoimmune
hypoparathyroidism.
• Hypoparathyroidism causes
hypocalcemia.
• Symptoms of hypocalcemia: Reduction in
potential difference at neuromuscular
membranes causes increased
neuromuscular irritability (i.e., tingling and
tetany).
• Patients also have cardiac arrhythmias. 64
 Adrenal gland
• Located on superior
surface of kidney
• Adrenal medulla
– Secretes norepinephrine &
epinephrine
– Targets sympathetic effector
organs
– Emotional arousal
• Adrenal cortex
– Aldosterone
– Cortisol
– Sex steroid
( androgen , esterogen)
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 Adrenocortical hyperfunction
(hyperadrenalism) :
The syndromes of adrenal hyperfunction
are caused by overproduction of the
three major hormones of the adrenal
cortex:
1. Cushing syndrome
2. Hyperaldosteronism
3. Adrenogenital syndrome

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Cushing syndrome

• production of glucocortikoid 🡪🡪
• Causes :
1. administration of exogenous
corticosteroids (iatrogenic)
2. Primary hypothalamic pituitary
disease
3. Hypersecretion of cortisol in
adrenal
4. Secretion of ectopic ACTH in non
endocrine neoplasm 67
Pituitary Cushing syndrome (70%)
• Adenoma hipofise 🡪 ACTH
• Hyperplasia hipofise 🡪
Lab : - ACTH 🡪
- cortisol 🡪
Adrenal Cushing syndrome (5-10%)
• Adenoma / carcinoma adrenal
• Hyperplasia adrenal
Lab: - cortisol 🡪
- ACTH 🡪
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Paraneoplastic Cushing syndrome

• Small cel Ca of the lung

• Carcinoid tumor
• Medullary Ca thyroid
• Islet cell Ca pancreas
Lab : - cortisol 🡪
- ACTH 🡪
(ec corticotropin releasing
factor from the tumor)

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Cushing syndrome

Symptoms and signs

• Hypertension
• Obesity, moon face,buffalo hump
• Reduced muscle mass in limbs
• Stria
• Increased hair growth
• Inhibition of uptake of glucose by cells leads to
hyperglycemia, glucosuria, and polydipsia.
• Resorption of bone, causing osteoporosis.

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Striae, hirsutism, central adiposity

Buffalo hump
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Adrenocortical Insufficiency

1. Primary acute adrenocortical

insufficiency (adrenal crysis)
2. Primary chronic adrenocortical
insufficiency (Addison Disease)
3. Secondary adrenocortical insufficiency

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Primary acute adrenocortical
insufficiency
Causes:
• Rapid withdrawal of exogenous steroids
• Acute exacerbation of chronic adrenal
insufficiency.
• As a result of massive adrenal hemorrhage
(Anticoagulant therapy, postoperative patients with DIC, and
pregnancy, Waterhouse-Friderichsen syndrome: sepsis due to
Neisseria meningitidis and Pseudomonas associated with
hemorrhagic necrosis of the adrenal glands)

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Primary acute adrenocortical
insufficiency
Clinical presentation:
• Symptoms: Severe abdominal pain,
nausea and vomiting, and somnolence.
• Signs: Hypotension.

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Primary chronic adrenocortical
insufficiency (Addison Disease)
• autoimmune disorder 🡪most common
cause of chronic primary adrenal
insufficiency in developed nations.
• Other causes of chronic adrenal
insufficiency: Metastatic tumor, infections
(e.g., tuberculosis,
AIDS,Histoplasma,Coccidioides immitis),
amyloidosis, and hemochromatosis.

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Primary chronic adrenocortical
insufficiency (Addison Disease)
Clinical presentation of chronic
adrenocortical insufficiency:
• Symptoms: Weakness, gastrointestinal
disturbances, weight loss
• Signs: Hyponatremia, hyperkalemia,
hypoglycemia, hypotension,decreased
aldosterone.

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ADRENAL NEOPLASMS

1. Adrenocortical adenoma
• Most adrenal
adenomas are
nonfunctioning

• Morphology: Yellow
nodule in adrenal
cortex.
• Microscopic: adenomas are composed of cells
similar to those populating the normal adrenal
cortex. The nuclei tend to be small, cytoplasm
of the neoplastic cells ranges from eosinophilic
to vacuolated, depending on their lipid content
ADRENAL NEOPLASMS
2. Adrenocortical carcinoma
• Gross: typically variegated, poorly demarcated
lesions containing areas of necrosis, hemorrhage,
and cystic change
• Microscopic: large, infiltrative, have fibrous bands
and necrosis, and cells with less cytoplasm and
more atypia including atypical mitotic figures
ADRENAL NEOPLASMS
3. Pheochromocytoma
• A tumor of the adrenal medulla that secretes
epinephrine and norepinephrine, causing
episodic hypertension.
• Associated conditions : MEN 2A and 2B, von-
Hippel Lindau syndrome, von Recklinghausen
disease of bone, and Sturge-Weber syndrome.
ADRENAL NEOPLASMS
• Microscopic: Bland, monomorphous cells in
nests (referred to as Zellballen pattern);
nuclei have salt and pepper chromatin.
Pheochromocytoma. A, The
mass in the adrenal medulla
is a pheochromocytoma. B,
Histologically,
pheochromocytomas
appear as bland
monomorphic cells in nests
(the “zellballen”
pattern.Hematoxylin and
eosin, 40.

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