Pituitary Gland Pathology

1. ANTERIOR Pituitary :

Secretes trophic hormones (trophic mean target another gland to secrete another
hormone)
Acidophil cells (pink in color); somatotroph, prolactin
Basophil cells (blue in color); corticotroph, gonadotroph, thyrotroph.
Under influence of feedback; +ve from hypothalamus and -ve from the body.
Most are stimulatory factors except for prolactin.
Most diseases arise from the pituitary itself (not hypothalamus)

FUNCTIONING Abnormality :
A) Hyperpituitarism :

Excessive secretion of one or more of hormones.

Most common cause: functional adenoma (benign tumor).
Then: hyperplasia, carcinoma, exogenous source (like from therapy)
Few adenomas are bilineage (GH + prolactin)

B) Hypopituitarism :

Deficiency of one or more of pituitary hormones.

Damage to more than 75% of anterior pituitary gland.
Most common cause: non-functional adenoma (it might be not-synthesizing or
non-secretory)

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Others: congenital dysgensis, ischemia (specific to pituitary called;

Sheehan syndrome occur post-partum), surgery, radiation, inflammatory
diseases (ex. Sarcoidosis), bone diseases.
Pituitary tumors causes damage to optic nerve (bitemporal heianopsia) and
increase intracranial pressure (headache, nausea, vomit)

 Pituitary adenoma :

Classified according to the cell origin, with corresponding hormonal synthesis.

Mostly develop in middle aged adults (30-50 years).
75% functional, secreting (one or more hormone)
25% functional, silent (synthesizing but not-secreting)
rarely hormone negative (non-synthesizing at all)
Most are sporadic, 3% are syndromic (multiple endocrine neoplasia).
(sporadic mean come in individual, no family Hx and it wont pass to the 2nd
generation)
<1 cm called micro-adenoma (symptom related to the secretion)
>1 cm called macro-adenoma; (symptom related to the mass; optic nerve
damage bitemporal heianopsia & increased intracranial pressure headache,
nausea, vomit )
Up to 20% of healthy adults have silent micro-PA (3 mm).

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Pathogenesis :
- Mutation in G-proteins that transmit a signal transduction to intracellular
effectors (adenyl-cyclase), generating 2nd messengers cAMP, a potent
mitogenic factor.
- Normally, G-proteins are activated upon ligand binding.
- Mutant G-proteins have autonomous, permanent activity (activation
without ligand).

A) Prolactinoma
Most common PA.

Cau
ses

galactorrhea, amenorrhea, loss of libido and infertility.

Symptoms appear obviously in menstrual and premenopausal women than in
men and postmenopausal women
Stalk effect: any interruption in hypothalamus-pituitary axis would cause
prolactinoma.

B) Growth Hormone-Producing Adenomas

Second most common

Secrete little amount of GH, at the time of symptoms it mean the adenoma is
advanced = large.
Very Big + Functional adenoma = most likely it is related to growth hormone
adenoma.
GH stimulates secretion of insulin-like growth factor-1 from liver.
Gigantism in children, Acromegaly in adults (face, hands, feet, soft tissue).
Also develops hypertension, heart failure, diabetes.

C) Corticotroph Cell Adenomas

Most are small at the time of diagnosis

very sensitive (secrete small amount of hormone causing symptoms in
contrast to GH-adenoma)
CUSHING DISEASE: bilateral adrenal enlargement.
NELSON SYNDROME: develop after bilateral adrenalectomy (no negative
feedback from the body), clinically aggressive.
Hyperpigmentation characteristic for CCA because ACTH & MSH share
precursor

D) Thyrotroph & Gonadotroph

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Rare, Produce little amount of hormones, usually symptoms are related to

mass effect.

2. POSTERIOR Pituitary

Secretes anti diuretic hormone (ADH), Acts on kidneys to promote reabsorption of

water.
ADH deficiency is called DIABETES INSIPIDUS (polyuria, polydipsia, dilute urine,
hypernatremia), caused by head trauma, tumors or surgery.
Excessive ADH is called SIADH (hyponatremia causing brain edema which may
lead to death), mostly secondary to paraneoplastic syndrome (small cell
carcinoma of lung; because they secrete ADH).

Thyroid Gland Pathology

The Diseases associated with increased OR decreased function & Tumors.
A) Thyrotoxicosis :

It is elevation of circulating free T3 and T4 leading to Hypermetabolic state.

Mostly secondary to hyperthyroidism (increased function of thyroid gland),
less common: exogenous source (as intake of thyroid drug) or thyroiditis

Causes :
Associated with hyperthyroidism

Primary :
1) Diffuse toxic hyperplasia (Graves
Diseasea)
2) Hyper-functioning (toxic)
multinodular goiter
3) Hyper-functioning (toxic) adenoma
Secondary :
1) TSH-secreting pituitary adenoma
rare

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1)
2)
3)

4)

Not associated with

hyperthyroidism
Subacute granulomatous thyroiditis
(painful)
Subacute lymphocytic thyroiditis
(painless)
Struma ovarii ovarian teratoma with
thyroid tissue also called ectopic
thyroid
Factitious thyrotoxicosis (exogenous
thyroxine intake)

Symptoms :
- Heat intolerance, excessive sweating.
- Skin: soft, flushed, warm
- Muscles (characteristic): proximal upper and lower muscle weakness.
- Cardiac (most dangerous): arrhythmia, palpitation.
- GIT: soft diarrhea, malabsorption, weight loss.
- Nervousness, irritability, increased sympathetic stimulation, tremor.

Ocular: lid lag, wide staring eyes (most obvious in Graves disease)

Apathetic hyperthyroidism: asymptomatic, in elderly because there

metabolism is normally low, only diagnosed by blood test.
Extreme situation called Thyroid storm = life-threatening.

ost obvious in Graves disease, secondary to accumulation of soft tissue behind the eye globes

B) Hypothyroidism :

Low level of circulating T3 & T4 leading to hypometabolic state.

Very important to check pregnant women (cause the baby depend on his
mother thyroid) and the baby at birth for thyroid function because it may lead
to mental retardation
Cretinism: infants or early childhood (low iodine, inborn enzymatic errors),
impaired skeletal, mental retardation, short stature, coarse faces, protruding
tongue.
Myxedema: adult, cold intolerance, bradycardia, heart failure, constipation,
weight gain, slow mental process, apathy, anemia.
Causes :

Primary
1) Post-ablative: surgery, radioiodine therapy or external radiation.
2) Hashimoto thyroiditis*
3) Iodine deficiency*
4) Dyshormonogenetic goiter (Congenital biosynthetic defect)*
5) Drugs: lithium, iodides, p-aminosalicyclic acid*
6) Thyroid dysgenesis (Rare developmental abnormalities of the thyroid)

Post-ablative & Hashimoto thyroidism are the vast majority of

hypothyroidism cases in adequate dietary iodine region.
* = Associated with enlargement of thyroid (goitrous hypothyroidism)
Secondary
Pituitary or hypothalamic failure (uncommon)

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 Chronic Lymphocytic (Hashimoto) Thyroiditis

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Most common cause of hypothyroidism

Autoimmune disease
Peak incidence 45-65
10 times more in women than in men because autoimmune diseases more
prevalent in females

Pathogenesis
- Progressive depletion of epithelial cells, replaced by inflammatory cells
(lymphocytes and plasma cells).
- Abnormality begin with; Autoreactive CD4+ T-lymphocytes against normal
thyroid antigens produces INF- Recruitment of macrophages, CD8+ T
lymphocytes, causing damage to epithelium.
- Also activate plasma cells of B-lymphocyte to synthesize auto antibodies
(diagnosis by the AB)
- Genetic predisposition (not hereditary): family history, HLA-DR3, HLA-DR5

Clinical
- Painless goiter
- Initial transient phase of thyrotoxicosis. Followed by gradual, progressive
hypothyroidism.
- Risk of B-cell lymphomas but NOT thyroid carcinoma.
- Other autoimmune diseases are common (like; lopus arthritis, immune
gastritis, )

Morphology
- Grossly: diffuse enlargement of thyroid gland, Intact capsule, Not
adherent to adjacent structures.
- Micro: dense infiltration of B-lymphocyte (forming germinal centers),
plasma cells, T-lymphocytes and macrophages.
- Follicular epithelium is atrophic, show metaplastic changes into larger, pink
cuboidal cells (full of mitochondria) called HURTHLE CELLS or OXYFIL CELLS
- With disease advance: fibrosis and atrophy.

Graves disease

Most common cause of hyperthyroidism

Autoimmune disease
20-40 years, females 7 times more than

males.
Triad: thyrotoxicosis, ophthalmopathy, localized infiltrative dermatopathy

(called pretibial myxedema, minority of patients)

Genetic predisposition (family history, HLA-DR3 and B8, other autoimmune

diseases
Transient episodes of hypothyroidism within the course of the disease.

On the left; pink follicle (Hurthle cell)

On the right; germinal center

Pathogenesis
-

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Break in CD4 tolerance against normal thyroid antigens Activates mainly

B-lymphocytes to secrete auto antibodies, Also responsible for the
infiltrative ophthalmopathy. Types of AB:

a) Thyroid-stimulating immunoglobulin (TSI): most important, autoAB that binds TSH receptor and mimics action of TSH, stimulating
adenylyl cyclase, results in secretion of thyroid hormones (specific)
b) Thyroid growth-stimulating immunoglobulins (TGI): another AB
against TSH receptor, stimulates proliferation of follicular epithelium =
goiter
c) TSH-binding inhibitor immunoglobulins (TBII): prevents TSH from
normal binding to its receptor and:
I. stimulates proliferation of follicular epitheliem,
II. other forms inhibit thyroid function (coexist)
Thats why graves disease may have episode of hypothyroidism.
d) Anti-thyroglobulin, anti-thyroid peroxidase Abs (not specific)
related to hashimito dis.

Infiltrative ophthalmopathy :
-

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Increased size of extra orbital muscles and retro orbital soft tissue causing
exophthalmos by:
a) Infiltration by inflammatory cells
b) Inflammatory edema
c) Accumulation of extracellular matrix (hyaluronic acid and chondroitin
sulfate)
d) Increased fat cells
Exophthalmos is irreversible even post treatment

Morphology:
- Diffuse goiter, soft, non-adherent, intact capsule
- Micro: follicular epithelial cells are hyperplastic (tall columnar, crowded
formation of small papillae, project into follicular lumen, lack fibrovascular
cores)
- Colloid is pale, scalloped margins
- Lymphoid infiltrate in between the cells (T > B-cells & plasma cells),
germinal centers
- Skin: edema, lymphocytes, glycosaminoglycans (hyaluronic acid and
chondroitin sulfate)

 Subacute Granulomatous (de Quervain) Thyroiditis

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More common in women

Most common 30-50 year old.
Viral infection or post viral inflammation (history of upper respiratory tract
infection)
Self-limited, not progressive.
Clinical & Morphology :
- Diagnosis is clinically

Acute painful goiter, could be asymmetrical, not adherent.

Fever, malaise, transient hyperthyroidism, leukocytosis.

Micro: disruption of thyroid follicles, infiltration begin by granulocytes

followed by lymphocytes, plasma cells and macrophages
(different than hashimoto they do not form germinal center)
Extravasated colloid initiates foreign body reaction forming granulomas

Subacute Lymphocytic Thyroiditis

Silent, painless, No or minimal goiter

Develop in post-partum women
auto immune, initial thyrotoxicosis then euthyroid, return in future
pregnancies.
Diagnosis is clinically
Micro: lymphocytic infiltrate, germinal centers and NO Hurthle cells.

Riedel thyroiditis

Rare, chronic, Unknown etiology, autoimmune??

Progressive fibrosis of thyroid and surrounding structures (adherent)
Hard goiter mimicking cancer.
Associated with fibrosis in other organs (retroperitoneum as pancreas, kidney,
Aorta)
Micro: thick fibrous bands, minimal follicles

Palpation thyroiditis :

It is result from Vigorous clinical palpation of the thyroid gland.

Results in multifocal follicular disruption associated with chronic inflammatory
cells and occasional giant-cell formation
Unlike de quervain thyroiditis, abnormalities of thyroid function are not
present, and palpation thyroiditis is usually an incidental finding in specimens
resected for other reasons
Asymptomatic.

Diffuse & multinodular goiter

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Reflects impaired synthesis of thyroid hormones, Commonly caused by iodine

deficiency.
Leads to compensatory rise in TSH causing hypertrophy & hyperplasia of
follicular epithelium goiter euthyroid.
Endemic goiter: it is 10% or more of population has goiter, in areas where soil,
water and food contain little iodine (Himalaya).
Sporadic goiter: mostly idiopathic, others: excessive calcium, cabbage,
cauliflower uptake, enzymatic deficiency.

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Clinical :
- The main complaint is mass in the neck (cosmetic, stridor, dysphagia,
compression of vessels)
- Not adherent
- Plummer syndrome: when toxic nodule produces hyperthyroidism (no
ocular disease)
- Some patients have hypothyroidism
- So, it can be euthyroid, hyperthyroidism or hypothyroidism.

Morphology :
- Early: diffuse goiter, similar to Graves disease
- When euthyroid status is reached, TSH decreases, follicular epithelium
becomes small and flat, with predominance of colloid (colloid nodule).
- Normally: follicular epithelial cells are heterogeneous in response to TSH
(some respond more than others)
- With repeated attacks, proliferation is variable, fibrosis, hemorrhage, cystic
degeneration, calcification goiter is irregular (multinodular goiter)
- Some nodules become dominant & secrete excess hormones (toxic nodule)
- Both mono & polyclonal nodules are present.

 Benign tumors : Follicular adenoma

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Benign neoplasm of follicular epithelium

Solitary (resemble the toxic nodule)
Mostly non-functional (cold nodule)
Clinically and radiology Might be difficult to distinguish from hyperplastic
(toxic) nodule or carcinoma, the diagnosis is by pathology (under the
Microscope).

Pathogenesis :
a) Activating mutation in TSH receptor or -subunit causing overproduction of
cAMP cell growth and mitosis
Rarely, can be functional and produce hyperthyroidism
b) 20% of cases have RAS mutation (also present in 50% of carcinoma)

Morphology :
- Solitary, well demarcated mass with intact, thin capsule (not present in
hyperplastic nodules)
- Micro: uniform follicles contain colloid distinct from the rest of thyroid, cells
are uniform
- If follicular cells show Hurthle cell change, called Hurthle cell adenoma
- Atypia might be present, but does not mean malignancy (Atypia is normally
common in endocrine system)
- If capsular invasion is present follicular carcinoma

Thy
roid

Carcinoma :

Rare, Early adulthood, women (estrogen receptors)

Old and pediatric cases might occur, risk factors (radiation)
Types; Papillary carcinoma, follicular carcinoma, Medullary carcinoma &
Anaplastic carcinomas.
All derived from the follicular epithelium, except for medullary carcinomas (Ccell)

A) PAPILLARY CARCINOMA
o
o
o
o
o
o

Most common thyroid carcinoma (75 - 85%)

Arise at any age (mostly middle aged women)
Painless mass in neck, Solitary or multiple
History of previous ionizing irradiation
Commonly associated with local LN metastasis (does not affect the prognosis)
Indolent disease with 10 year survival >95% (one of the best human cancer
in prognosis)

o Pathogenesis
- 2 pathways, end by activating mitogen activating protein (MAP) kinase
signaling pathway:
I. of patient have BRAF gene mutation activating MAP.

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II.

20% of patient have mutation in RET gene rearrangement (tyrosine

kinase receptor), creating novel gene (ret/PTC) which activates RET
and MAP.
III. 10% Neurotropic tyrosine kinase receptor1 (NTRK1) mutation.
o Morphology (important)
- Well circumscribed, sometimes encapsulated
- Micro: special nuclear features:
Optically clear nuclei, called ground glass or Orphan Annie eye
Nuclear grooves (pseudo-inclusions) like coffee bean
Orphan
Annie
eye
- Papillary architecture; Tip of papillae because it far from blood
vessel
may
have ischemia and Calcification (psammoma body), cysts are common

B) FOLLICULAR CARCINOMA

o
Second most common carcinoma (10- 20%)
Older age than PTC.
Associated with; iodine deficiency & RAS mutation in 50%
Micro: normal looking follicles, may see Hurthle cells, capsular or
lymphovascular invasion.
Evaluating the integrity of the capsule is critical in distinguishing follicular
adenomas from follicular carcinomas.
o Clinically similar to MNG
o
o
o
o

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C) MEDULLARY CARCINOMA (5% )

Neuroendocrine neoplasm, arises from parafollicular cells (C-cells)
Increased blood level of calcitonin (but no hypocalcemia)
Sporadic in 80% of cases, old age
20% are familial (familial medullary thyroid carcinoma, or multiple endocrine
neoplasia), young age, aggressive disease, bad prognosis
o RET gene mutation
o
o
o
o

o Morphology
- Solitary tumor (sporadic) or multiple (familial)
- Micro: polygonal or spindle cells.
- Secrete amyloid (derived from calcitonin), positive for congo-red stain
- C-cell hyperplasia is in non-tumorous areas
- Electron microscopy: membrane bound granules containing calcitonin.

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D) ANAPLASTIC CARCINOMA
Rare disease (<5% )
Old age
History of multinodular goiter or PTC
P53 mutation
Very aggressive (one of the worst
carcinoma)
o Rapid growth and death within a year
o Cells are large, epithelioid or spindle,
pleomorphic
o
o
o
o
o

Parathyroid Gland Pathology

Most tumors are active, diagnosis is made after noticing hypercalcemia but
asymptomatic

PRIMARY HYPERPARATHYROIDISM :

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Very common
Causes silent hypercalcemia (in contrast to cancer) , incidentally finding.
80% of cases are secondary to adenoma (in one of the 4 parathyroid the rest
are atrophic),
15% hyperplasia (four glands), 5% carcinoma.
95% cases are sporadic, 5% familial (MEN)
Familial hypocalciuric hypercalcemia: rare disease, mutation in Ca sensing
receptor on parathyroid gland, leading to constitutive secretion of PTH.

Pathogenesis
- Parathyroid adenomatosis gene1 (PRAD1), cyclin gene.
- Cyclin D1 (another cyclin) in adenoma, hyperplasia and carcinoma.
- MEN1 gene (tumor suppressor) it mutation lead easy tumor progression.

Morphology
- Under the microscope they are identical, different in; how many gland
affected & weight.
- Adenoma: single large glands, the rest are atrophic, composed
predominantly of Chief cells, may show atypia, weight 0.5-5 gm
- Hyperplasia: more than one gland, chief cells, the combined weight usually
less than 1 g
- Carcinoma: single, adherent to neck, shows invasion, metastasis, weight
>5 g

SECONDARY HYPERPARATHYROIDISM :

Develops in patients with long standing hypocalcemia.

Most commonly seen in chronic renal failure (hyperphosphatemia suppresses

calcium level & also no activation of vitamin D no absorption of calcium

from guts)
Morphology: hyperplasia of the four glands, serum calcium then normalizes
If patient develop progressive and autonomous hypercalcemia (usually even
after a correction of the kidney by transplantation) it is called tertiary
hyperparathyroidism

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 HYPOPARATHYROIDISM

Rare
Results from surgical removal, congenital absence, autoimmune, fungal

infection
Patients develop hypocalcemia (muscle weakness, neuromuscular
abnormality)

Endocrine Pancreas Pathology

Diabetes mellitus: group of diseases that share a common feature of persistent
hyperglycemia.
Defect in insulin secretion, function or both resulting in damage to multiple
organs in the body.
Commonly cause; end-stage renal failure, adult onset blindness & non-traumatic
L-limb amputation.
INSULIN FUNCTIONS
- Increase uptake of glucose in skeletal, cardiac muscles (stored as glycogen)
and adipocytes (stored as fat), both forming 2/3 of body weight.
- Inhibit fat & glycogen degradation
- Reduce production of glucose from liver

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Promote amino acid uptake into muscles & protein synthesis, inhibit
degradation
Promote DNA synthesis, cell growth & differentiation
In fasting state, insulin is low

Type 1 DM

Characterized by an absolute deficiency of insulin secretion caused by

pancreatic -cell destruction, usually resulting from an autoimmune attack
(insulitis) Break in tolerance to -cells or insulin
10% of all cases.
Begins in childhood, manifests in adolescence (abrupt onset)
Genetic predisposition HLA-DR3 and HLA-DR4
CD4-T lymphocytes, secrete INF- activate CD8-T lymphocytes &
macrophages (secrete IL-1, TNF) damage -cells, also activate Blymphocytes to produce auto AB against insulin or -cells
Micro: -cell necrosis & lymphocytes infiltration (insuliti))
T-cell inhibitory receptor (CTLA-4)
Viral infection

Type 2 DM

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Caused by a combination of peripheral resistance to insulin action and an

inadequate compensatory response of insulin secretion by the cells
("relative insulin deficiency").

Obesity is strongly associated with DM

secretion of resistin and free fatty acid from adipocytes in obese (causing
insulin resistance)
& Decreased adiponectin secretion (insulin sensitizer) in obese

Thliazolinediones drug family activates PPAR gene in fat cells & reverse the
abnormalities
FFA & hyperglycemia adversely affects -cells both qualitatively (loss of
normal response to glucose ingestion) and quantitatively (loss of -cells &
deposition of islet cell amyloid (amilin)

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80% to 90% of cases.

Genetic + environmental (dietary habit)
Genes not related to immune tolerance or insulin signaling pathway (still
unknown)
Insulin resistance precedes DM by decades

 Monogenic DM :

A single genetic mutation causing DM (in contrast to most cases of types 1,2
are genetically complex (multiple susceptible foci)
Rare
Either affect -cell function (MODY genes) or cellular insulin signaling

Other causes of DM
Loss of pancreatic tissue (carcinoma, fibrosis)
Increased hormones antagonizing insulin: (GH, cortisol, glucagon, thyroxin,
adrenalins)
CMV, Coxsackie B pancreatitis
Syndromes: Down, Kleinfelter, Turner
Gestational diabetes (increased insulin requirement on a background of
resistance)
Drugs; -agonists (causing hyperglycemia)

Effect of hyperglycemia:
1. Non-enzymatic glycosylation of proteins (sticking or adhering of
glucose to protein)
a) Glycated hemoglobin (HgA1C): reflects history and degree of
hyperglycemia, because normally there is a low element of glycation,
which will rise in DM patient to >6% of total Hb, more rising the worse is
the hyperglycemia.
b) Glycated extracellular matrix in vessels: collagen will have permanent
changes (cross linking), called advanced glycosylation end products
(AGEs), causing entrapment of plasma proteins (lipoproteins), causing
accelerated atherosclerosis.
c) In renal glomeruli, glycated basement membrane becomes thickened &
entraps albumin.

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d) glycated serum proteins are entrapped in endothelium, causing release of

cytokines & growth factors. In the kidney, causes increased endothelial
permeability, mesangial proliferation & synthesis of extracellular matrix.
2. Activation of protein C
o Secondary to cytoplasmic hyperglycemia
o Activated protein C produces transforming growth factor (TGF-), causing
angiogenesis
o Increased deposition of extracellular matrix and basement membrane
o critical in retina = blindness
3. Intracellular hyperglycemia with disturbance in polyol pathways
o Important in organs that are insulin independent (brain, nerves, vessels,
lens, kidneys)
o Intracellular glucose is metabolized into sorbitol & fructose increasing
intracellular osmolality & water influx swelling
o Sorbitol metabolism depletes cellular anti-oxidants cell damage.

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 PANCREATIC ENDOCRINE NEOPLASMS

PEN, or islet cell tumor

2% of pancreatic tumors
Present in adulthood
Single or multiple
Functional or non-functional
Benign (commonly <2 cm) or malignant (metastasis to LN and liver)

A) Insulinoma

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-cell tumor, most common PEN.

90% are benign, solitary, functional.
Recurrent attacks of hypoglycemia, affecting CNS, precipitated by fasting &
exercise.
20% have severe symptoms, can be fatal

Micro: proliferation of islets of neuroendocrine cells, uniform and monotonous

(similar to normal cell even in malignant, no anaplasia, differentiate by
function or stain).
Positive for insulin immunohistochemically stain (brown in color)

B) Gastrinoma

Produced by gastrinoma triangle: pancreas, peripancreatic soft tissue &

duodenum.
90% of patients develop severe, multiple peptic ulcers (Zollinger-Ellison
syndrome), refractory to ordinary therapy
50% show invasion & metastasis, 25% are syndromic (MEN 1) & multiple.
Similar histology to insulinoma

C) Glucagonoma

-cell tumor
Increased serum glucagon resulting in mild diabetes.
Most common in peri & post-menopausal women
Commonly have characteristic skin rash (necrolytic migratory erythema)
mostly in face, U-limb
Unknown cause, a theory; deficiency in nutrient secondary to increase
glucagon mostly the zinc.
Similar histology to insulinoma

Adrenal Gland Pathology

A) The Zona Fasciculate; Hypercortisolism :

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Increased glucocorticoid levels in blood

Most common cause: exogenous administration then; Corticotroph pituitary
adenoma (Cushing disease), Primary adrenocortical hyperplasia,
Adrenocortical adenoma, carcinoma, Ectopic ACTH of non-endocrine neoplasm

 Cushing syndrome
o
o
o
o

Primary adrenocortical origin

Elevated serum cortisol and low ACTH
Most common cause is unilateral adrenocortical neoplasm
Primary bilateral hyperplasia is rare, 2 types:
- Macro-nodular growth (>3 mm) usually acquired later in life
- Micro-nodular, pigmented, familial (early in life), other endocrine
hyperplasia

Ectopic ACTH :
o Paraneoplastic syndrome
1. Small cell carcinoma of lung (most common)
2. Carcinoid
3. Medullary thyroid carcinoma.
4. Islet cell tumor of pancreas.
5. Ectopic corticotrophin releasing hormone (CRH)

Morphology
o Pituitary gland: Crooke hyaline change or Crooke bodies: homogenous light
basophilic intracytoplasmic material, composed of intermediate keratin
filaments. The normal granular basophilic cytoplasm of corticotroph cells is
lost due continuous negative feedback.
o Exogenous or ectopic cortisol: bilateral cortical atrophy in adrenals
(atrophy of fasciculata & reticularis)
o Adrenal hyperplasia: diffuse thickening of the cortex, may show multiple &
bilateral 0.5-2cm nodules (nodular hyperplasia). Combined adrenal weight
30-50 g

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 Adrenocortical adenoma :

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Single, encapsulated, yellow mass, Weight 30g

Micro: similar to normal zona fasciculate which contain vacuoles full of lipid.
Can be non-functioning (called incidentalinoma) found incidentally.
If functioning, the other adrenal is atrophic

 Adrenocortical carcinoma

Large, not capsulated, weight 200 g

Micro: anaplastic cells, hemorrhage, necrosis.
Can be functioning or not.
If functioning, the other adrenal is atrophic
Mostly are Sporadic or syndromic as; Li-Fraumeni mutation in p53 which
tumor suppressor & Beckwith-Weidman.
Metastasis to lymph nodes, lung, but NOT bone.
Clinical features:
- Insidious, chronic onset (except for small cell carcinoma)
- Early: weight gain (central, moon face), hypertension.
- Muscle atrophy
- Hyperglycemia (inhibit uptake of glucose)
- Hyperpigmentation (more obivious in cushing dis.)
- Hirsutism.
- Mood disturbance (depression).
- Menstrual abnormality.

B) The Zone Granulosa; Hyperaldosteronism :

Hypernatremia, hypokalemia, hypertension

Primary hyperaldosteronism :

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Adenoma (80% of cases), Conn syndrome. characterized by low serum renin

Adenoma is solitary, encapsulated, <2 cm
No suppression of ACTH (ACTH in normal level), second adrenal is not
atrophic.
Micro: Adenoma: lipid laden (resemble fasciculate rather than granulosa),
contain eosinophilic laminated cytoplasmic inclusions (spironolactone bodies)

due to most patient using diuresis for hypertension without investigation

because mostly it is idiopathic, leading to accumulation of the diuretics
(spironolactone) in the adrenal.

Hyperplasia 19% (over activation of CYP11B2 gene), also characterized by

low serum renin
Hyperplasia: bilateral, enlarge, nodular.

Carcinoma is rare, NO exogenous.

Q: What causing adrenal mass with normal ACTH level?

A: conn syndrome OR non-functional adenoma.

Secondary hyperaldosteronism

Always associated with high renin in serum which caused by hypovolemia

Decreased renal perfusion (renal artery stenosis)
Nephrotic syndrome, congestive heart failure, cirrhosis. Those diseases
accumulate the fluid in the interstitial hypovolemia
Pregnancy (estrogen induced)

C) The Zone Reticularis; Adrenogenital syndromes :

Adrenal androgens are under the influence of ACTH (in contrast to gonads)
Increased production, with virilization, is commonly seen in adrenocortical
neoplasms (especially carcinoma) because some of the increased cortisol will
turn to androgens.

CONGENITAL ADRENAL HYPERPLASIA :

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Autosomal Recessive; affect both sexes

CYP21B gene mutation
21-hydroxylase enzyme deficiency (range from mild to total loss)
Low production of cortisol, High ACTH.
Accumulation of cortisol precursors Shift to androgens virilization,
ambiguous genitalia in females, weight loss, early puberty
Morphology: bilateral large adrenals, brown in color (depletion of lipid)

 Adrenal insufficiency

Types; Primary acute insufficiency, Primary chronic insufficiency & Secondary

insufficiency.
Clinical symptoms appear after 90% reduction in adrenal size.
hyperkalemia, hyponatremia, hypotension, hypoglycemia, fatigue, nausea,
vomiting, Weight loss.

1.

Acute insufficiency; causes:

o Sudden withdrawal of long-term steroid therapy.
o Acute (stress) on top of chronic insufficiency
o Massive adrenal hemorrhage
o Waterhouse-Friderichsen syndrome : bilateral adrenal damage secondary to
bacterial infection (Neisseria meningitidis, pseudomonas sepsis)

2.

Chronic insufficiency; causes:

o Addison disease, Autoimmune adrenalitis (70%), AIDS, TB, Metastatic
cancer (lung, breast)
o Characterized by high ACTH, skin hyperpigmentation.

3.

Secondary insufficiency; causes:

o Low production of ACTH from pituitary, Any disease in hypothalamus pituitary
axis
o Low ACTH, NO hyperpigmentation, other pituitary hormone(s) deficiency

Pheochromocytoma :

Tumor of chromaffin cells, adrenal medulla.

Synthesize and secrete Catecholamines
Refractory hypertension (very bad)
10% familial (MEN syndrome), 10% bilateral, 10% extra-adrenal
(paraganglioma), 10% malignant.

Micro: zellballen pattern (small balls), finely granular cytoplasm positive for
silver stain.

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Mitosis, pleomorphism, polygonal and spindle cells, lymphatic and vascular

permeation can be seen in benign lesion.
Metastasis is the definite diagnosis for malignancy, Because the normal,
benign, malignant can look the same.

Multiple Endocrine Neoplasia (MEN)

1) MEN type 1

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Autosomal Dominant.
The patient born with single mutation, later in life, Inactivation of both alleles
of MEN1 gene, located on 11q13 (tumor suppressor gene) then the symptom
start.
Multiple parathyroid hyperplasia (95%)
Pancreas (40%), often functional (insulinoma, gastrinoma), fatal
hypoglycemia, behave aggressively with metastasis

Pituitary (30%), prolactinoma is most common

2) MEN type 2

Activating mutation in RET proto-oncogene on 10q11.2

The type of mutation strongly affects the clinical severity
Genetic testing for RET mutation if member of the family has mutation.
Prophylactic thyroidectomy should be done because 100% they will develop
medullary thyroid cancer which is aggressive.
A. MEN type 2A
o Medullary thyroid carcinoma (100%), in the 1st two decades of life, C-cell
hyperplasia
o Adrenal medulla: 50% develop Pheochromocytoma
o Parathyroid: develop hyperplasia
B. MEN type 2B
o Similar to MEN 2A, but no parathyroid hyperplasia
o Develop ganglioneuroma of mucosal sites (GI)
o Marfan-like features.

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