- System of ductless glands.
- Hormones secreted into the bloodstream.
- Orchestrate a state of metabolic equilibrium or homeostasis.
- 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, paracrine or autocrine.
- Exocrine - ducted; carry secretion to outside surface, eg. sweat (eccrine), sebaceous, mammary, digestive (pancreas, liver, gall bladder), etc.
- Endocrine - ductless; secrete into interstitial fluid, diffuse into blood.
- Pituitary, thyroid, parathyroid, adrenal, pineal glands.
- Hypothalamus, thymus, pancreas, ovaries, testes, kidneys, stomach, liver, small intestine, skin, heart, adipose tissue, placenta - NOT exclusively endocrine glands.
Transportation of Hormones
- Bounded to plasma proteins such as thyroid and steroid (they serve as a reserve for acute changes).
- Some are transported free in the blood.
- Only free hormones are biological active
General characteristic of hormones
- Specific rates and patterns of secretion: diurnal, pulsatile, cyclic patterns, depending on the level of circulating substrates.
- Feedback systems: positive (rare) or negative, to maintain an optimal internal environment.
- Affect only cells with appropriate receptors -> specific cell function(s) is initiated
- Excreted by the kidney, deactivated by the liver or by other mechanisms
Functions of endocrine system
- Response to stress and injury
- Growth and development
- Energy metabolism
Diseases divided into
- Hyperfunction - overproduction
- Hypofunction - underproduction
- Mass effects (Tumors) - nonfunctioning
- Correlation of hormonal assays, clinical, biochemical, and pathological findings, are of extreme importance in most conditions.
Exocrine (digestive enzymes) as well endocrine (hormones such as insulin).
- Location - retro-peritoneum, 2nd lumbar vertebral level.
- Extends in an oblique, transverse position.
- Parts of pancreas: head, neck, body and tail. Most Islet of Langerhans cells are located in the body and tail; the part to look at when there is a tumor.
Islet of Langerhans
- One million islets of Langerhans
- Different types of cells can be identified immunohistologically.
- α cells - glucagon; stimulates Glucose synthesis & glycogen breakdown in liver; raise blood glucose concentration (normal level ~ 0.9 gram per Liter).
- β cells - insulin; Stimulation of lipids & glycogen storage & formation; Lower blood glucose concentration.
- δ cells - somatostatin; Inhibits secretion of insulin & glucagon. Pancreatic polypeptide (PP) becomes VIP (vasoactive interstitial polypeptide
Islet cell diseases
- Islet Cell Tumors
- Metabolic disorders
- Defects in insulin secretion, or insulin action, or most commonly, both.
- Accelerates atherosclerosis, hypertension and Affects multiple organ systems - kidneys, eyes, nerves and blood vessels
- Affects over 20 million in adults and children.
- Leading cause of end stage liver disease, adult-onset blindness and non-traumatic lower extremity amputation in US.
- Causes could be Primary in the pancreas or secondary to other disease conditions
- Primary diabetes is classified into :
- A- Type 1 (approximately 10%)
- B- Type 2 (approximately 90%)
- C- Genetic & Miscellaneous causes
- Whatever the type, complications are the same.
- Develops in childhood.
- Autoimmune destruction of islet cells
- Insulitis - Heavy lymphocytic (CD4, CD8) infiltrates appear in and around islets.
- The islets of Langerhans are destroyed (90% of cells lost before metabolic changes appear)
- Polyuria , Polydipsia, Polyphagia (3P’s)
- Metabolic acidosis, weight loss, dehydration, & electrolyte imbalance.
- Ketoacidosis is common.
- Age > 30yrs, often present incidentally
- Sedentary life style and overweight
- Insulin resistance & β cells dysfunction , resulting in relative insulin deficiency
- Fibrosis and deposition of amylin polypeptide within islets: amyloid deposition; very few islet cells left
- 3 P’s and symptoms of complications
- Rare ketoacidosis
Secondary Miscellaneous Causes
- Diseases of exocrine pancreas e.g. chronic pancreatitis
- Endocrinopathies e.g. Cushing’s Syndrome, Acromegaly
- Infections e.g. CMV
- Drugs e.g. glucocorticoids
- Gestational diabetes
Common differences between type 1 and type 2 diabetes
- Age of diagnosis: childhood vs. 30 plus
- Associated with obesity: no vs. yes
- Blood pressure and/or cholesterol level: normal vs. high
- Ketone level: high vs. normal
- Insulin dependent: yes vs. no
- Treatment: insulin injection/pump vs. no medication or insulin tablets.
- Random glucose over 2gram per Liter + symptoms.
- Fasting glucose over 1.26gram per Liter on more
- than one occasion.
- Abnormal oral glucose tolerance test when glucose level is more than 2 gram per Liter 2hrs after standard glucose load of 75 gram.
Diagnosis Glycosylated Hemoglobin - H b A 1 c
- Measures the amount of glucose that has been incorporated into the hemoglobin protein of the red blood cell (RBC).
- More stable than sugar levels.
- Not affected by short-term fluctuations in sugar.
- Normal is 4-6%.
- Evaluated periodically (1-2 per year).
Blood test levels for diagnosis of Diabetes and Prediabetes
- A1C %
- - Normal ~5
- - Prediabetes 5.7-6.4
- - Diabetes 6.5 or above
- Fasting plasma glucose mg/dl
- - Normal no more than 99
- - Prediabetes 100-125
- - Diabetes 126 or above
- Oral glucose Tolerance test mg/dl
- - Normal no more than 139
- - Prediabetes 140-199
- - Diabetes 200 or above
Complications of diabetes
- Microangiopathy - cerebral vascular infarcts; hemorrhage
- Retinophathy - cataracts; glaucoma
- Nephrosclerosis - glomerulosclerosis
- Peripheral vascular atherosclerosis - gangrene, infections
- Both nodular (Kimmelstiel - Wilson lesion) and diffuse glomerulosclerosis
- Chronic renal failure eventually
- Infections – pyelonephritis (bacterial and fungal infections)
Ocular Complications - Diabetic retinopathy
- One of the leading causes for irreversible blindness in the United States
- Cataract - developed at very early age
- Early and accelerated atherosclerosis
- Heart disease, cerebrovascular disease, and renal disease
- The most common cause of death - myocardial infarction
- Peripheral vascular disease - gangrene leg and amputation
- Diabetic neuropathy, leading to propensity for injury
Diabetes Mellitus Treatment
- Type 1: insulin administration
- Type 2: diet & exercise
- - Oral hypoglycemics
- - Insulin
Pancreatic Neuroendocrine Tumors (PanNETs)
- a.k.a. Islet cell tumors
- 2% of all pancreatic neoplasms
- Common in adults, in body or tail
- Single or multifocal
- Functional (excessive hormone production) and nonfunctional (without hormone production; larger and metastasize)
- Slow growing, metastases to nodes, liver, bone.
- 80% occur in MEN1 patients.
- Insulinoma: most common; followed by gastrinoma
Types of Islet cell tumors
- Insulinoma – Beta cells; insulin-secreting tumor
- Gastrinoma – Delta cells
- Somasostatinoma – Delta cells
- Glucagonoma – Alpha cells
- VIPoma – Delta cells
Islet cell tumor Histology
- Solid, gyriform, trabecular and glandular patterns.
- Nests of polygonal cells with moderate to abundant eosinophilic cytoplasm.
- Amyloid is produced by insulin-secreting tumors (from amylin or somatostatin).
- Immunostains not necessary for diagnosis.
- - Synaptophysin
- - Chromogranin
- - Insulin
- - EM – dense core granules
W.H.O. grading system
- Low grade (G1): <2 mitoses per 10 hpf (high power field) and <3% Ki67 (immunostain, discriminate cells according to cell cycle phases) index
- Intermediate grade (G2): 2-20 mitoses per 10 HPF or 3%-20% Ki67 index
- High grade (G3): >20 mitoses per 10 hpf or >20% Ki67 index
- Commonest type.
- Hypoglycemia ≤ 0.5 gram per liter.
- Attack induced by fasting or exercise, relieved by eating or glucose administration
- Lab - low serum glucose, high serum insulin.
- Most tumors solitary (< 2 cm), can be multiple.
- Majority are benign, 10% malignant.
- 90% cured by resection.
- 2/3 of cases malignant.
- Present with Zollinger-Ellison Syndrome (triad - hypersecretion of gastric acid, severe peptic ulceration, and non-beta cell tumor of the pancreas or duodenum).
- Marked elevation of serum gastrin (>1000 pg/ml).
- Medical therapy for control of the acid hypersecretion.
- Histologically bland.
- May be associated with MEN1.
Nonfunctional islet cell tumors
- 25% of islet cell tumors
- 90% malignant
- Age 50 year, female predominance
- Compression related symptoms
- Treatment - surgery
- Normally on the posterior thyroid surface
- Most persons have four; may vary between 1 to 12.
- Well capsulated.
- Derivatives of third and fourth branchial pouches.
- Ectopic locations:
- - intrathyroid
- - intrathymic
- - anterior mediastinum
Histology of Parathyroid
- Chief cells – polygonal cells with clear cytoplasm (glycogen) and central uniform nuclei; secrete PTH.
- Oxyphil cells – larger than chief cells, acidophilic cytoplasm (pink), packed with mitochondria.
- Stromal fat – approximately 30% of the gland; increases when older.
Activity of parathyroid gland in regulating systemic calcium homeostasis is controlled by free (ionized) calcium rather than trophic hormones.
Normal calcium level
- Serum Calcium: 8 to 10 mg per dl
- Ionized (free) Calcium: 4 to 5.6 mg per dl
- increase plasma calcium level via
- - increase bone resorption.
- - lower renal phosphate reabsorption and increase calcium reabsorption.
- - increase intestinal calcium absorption (by stimulating renal secretion of 1,25-DH-viatmin D3).
Causes of hypercalcemia
- Raised PTH - Hyperparathyroidism (primary, secondary and tertiary); Parathyroid tumor. Normal level - 10-65 nmol per Liter.
- Decreased PTH (non-PTH)
- - Hypercalcemia of malignancy (most common, esp lung)
- - Vitamin D toxicity
- - Immobilization
- - Thiazide diuretics
- - Granulomatous disease (sarcoidosis)
- Normal PTH - 10 to 65 nanomoles per Liter.
- Increased parathyroid hormone.
- Serum calcium may be decreased, increased or normal, depending upon renal function.
- Primary hyperparathyroidism – excess of parathyroid hormone from adenoma (85 to 95%), hyperplasia (5 to 10%) or carcinoma (1%).
- Secondary hyperparathyroidism – adaptive increase in parathyroid hormone secondary to hypocalcemia and hyperphosphatemia of chronic renal failure.
- Tertiary hyperparathyroidism – autonomous parathyroid hyperfunction in patients with secondary hyperparathyroidism.
Parathyroid hormone and calcium in hyperparathyroidism
- Primary - normal or high PTH; high calcium.
- Secondary - high PTH; high or normal calcium.
- Tertiary - very high PTH; high calcium.
Hyperparathyroidism Signs / Symptoms
- Hypercalcemia, hypophosphatemia
- Asymptomatic mostly or present with nonspecfic symptoms such as fatigue, lethargy and muscle weakness.
- “Bones, stones, abdominal groans, psychic moans”
- Bones - pain, arthralgia - osteoporosis, osteitis fibrosa cystica (brown tumor, similar to the ones in jaw bones), fracture.
- Renal - Stones, polyuria, nephrocalcinosis.
- G.I. - Pain, duodenal ulcer, pancreatitis, gallstones.
- Neuro - Depression, apathy
- Cardiac - Hypertension, heart block
- Benign neoplasm.
- Involve a single gland, rarely two or more (<1%).
- Major cause of primary hyperparathyroidism.
- Any age, F:M 3:1.
- Excellent prognosis after excision.
- Sharply demarcated from the adjacent rim of normal parathyroid.
- Predominantly chief cells in sheets or tubules.
- Adipose tissue inconspicuous.
- Classically all four parathyroid involved (frequently asymmetrical).
- Sporadic or as a component of MEN syndrome.
- 75% sporadic
- 15% part of MEN 2A (not MEN 2B)
- 15% of hyperparathyroidism cases
- Diagnosis of adenoma versus hyperplasia may depend on the size of the other glands (one is adenoma, two or more is hyperplasia).
- Enlarged parathyroids.
- Usually chief cell hyperplasia, diffuse or nodular
- Variable oncocytes.
- Cystic change in markedly enlarged glands.
- Stromal fat inconspicuous.
- Palpable neck mass (75%)
- Excessive PTH secretion, high serum calcium > 14 mg/dl.
- Non-functioning tumors are rare.
- Diagnosis based on local invasion and metastases (clinical criteria, NOT microscopic criteria).
- 1/3 recur locally; 1/3 have distant metastases.
- Densely adherent to surrounding soft tissue.
- Thick fibrous bands.
- Predominantly chief cells arranged in solid or trabecular pattern.
- Macronucleoli, more than five mitoses per 50 hpf, necrosis associated with aggressive behavior.
- Cytological detail, unreliable for the diagnosis of carcinoma.
- Insufficient parathyroid hormone is secreted from the parathyroid glands, resulting in abnormally low levels of calcium in the blood.
- Hypoparathyroidism is far less common.
- – Damage to the gland or its vessels during thyroid surgery
- - Idiopathic, autoimmune disease, congenital
- Clinical features:
- - Tetany, convulsion, neuromuscular irritability, cardiac arrhythmias, increased intracranial pressure, seizures, ...
Multiple Endocrine Neoplasia
- MEN I (Wermer syndrome)
- - Neoplasia of Pituitary, Parathyroids, Pancreas and Carcinoids;
- - Parathyroid hyperplasia.
- MEN IIA (Sipple's syndrome)
- - Parathyroid hyperplasia
- - Medullary thyroid (c-cell) carcinoma
- - Pheochromocytomas.
- MEN IIB
- - Medullary thyroid (c-cell) carcinoma
- - Pheochromocytomas
- - Neuromas of eye, buccal mucosa and GI mucosa.
Thyroid gland anatomy
- Pyramidal lobe (present in 40% population)
- Left and right lobes
Thyroid gland Histology
- Follicles made of Colloid surrounded by follicular epithelial cells (squamous, cuboid, or columnar; secreting thyroid hormones - T3 and T4).
- Parafollicular cell (C cell; fewer and scattered) secretes calcitonin, can be picked up by calcitonin stain.
- Capillary in the connective tissue.
- Largest endocrine organ
- Thyroid hormones (TH)
- - Thyroxine (T4)
- - Triiodothyronine (T3)
- - Calcitonin
- Hypothalamus stimulates pituitory to release T.S.H. via T.R.H.
- Serum free hormone level inhibits pituitary to release T.S.H.
- T.S.H. stimulates thyroid to release T3 and T4
- liver releases thyroid binding proteins to bind T3/T4.
- Duct from Foramen cecum to suprasternal notch.
- Lingual thyroid - Most frequent; more in children; base of tongue with total migration failure; 75% have no other thyroid tissue.
- Other sites – anterior tongue, larynx, trachea, mediastinum, heart.
Thyroglossal duct cyst
- Persistence and dilatation of thyroglossal duct in midline of neck.
- Asymptomatic unless infected.
- Moves with swallowing.
- Squamous or respiratory epithelium lining cyst.
- - Loss of thyroid tissue due to surgery or radiation therapy
- - Hashimoto’s thyroiditis (most common cause in USA)
- - Iodine deficiency (in endemic areas; most common cause worldwide)
- - Drugs e.g. iodides, lithium…..
- - Pituitary or Hypothalamic failure
Hypothyroidism (underactive thyroid)
- High TSH, low T3, T4
- Hypothyroidism in infants – cretinism (poor growth, resulting in short stature, delayed development of permanent teeth, Delayed puberty, poor mental development).
- Hypothyroidism in adults - myxedema
- Treatment - Synthetic thyroid hormone
Classification of Thyroiditis
- Chronic lymphocytic
- - Chronic lymphocytic thyroiditis
- - Hashimoto's thyroiditis
- - Subacute granulomatous thyroiditis
- - de Quervain's thyroiditis
- Invasive fibrous
- - Riedel's struma
- - Riedel's thyroiditis
Hashimoto thyroiditis (Stuma Lymphomatosa)
- Most common cause of goiter in the United States.
- Autoimmune origin.
- Painless enlargement, no tenderness when palpated.
- Diffuse nontender rubbery thyroid enlargement.
- Variable functional status: euthyroid (normal serum level), hyperthyroid (Hashitoxicosis; when follicle ruptures and T3/4 released) or hypothyroid.
- Flashy cut surface.
- Histologic diagnostic triad:
- - lymphocytic infiltrate
- - lymphoid follicles with germinal centers
- - Hurthle cell metaplasia of follicular epithelium
- High risk for B-cell lymphoma, papillary carcinoma and Hurthle cell neoplasm
Subacute thyroiditis (granulomatous thyroiditis or De Quervain thyroiditis)
- Caused by viral infection.
- Most common cause of painful thyroid.
- Onset often acute, fever and malaise.
- Triphasic clinical course - hyperthyroidism, hypothyroidism, and return to normal thyroid function (within 6-8 weeks).
- Disruption of follicles with inflammation.
- Granulomatous reaction to colloid.
- Multinucleated giant cells.
Riedel’s thyroiditis (Riedel’s struma, fibrous thyroiditis)
- Autoimmune etiology.
- Stony hard painless thyroid gland.
- Extensive fibrosis.
- Clinically resembles carcinoma, compress trachea.
- Broad bands of fibrosis with keloid like fibers.
- Patchy lymphocytes, plasma cells and eosinophils.
- Follicles are obliterated.
- Obliterating phlebitis.
- Hypermetabolic state caused by T4, T3
- Primary: Graves Disease
- Secondary: TSH-secreting pituitary adenoma
Clinical Picture of Thyrotoxicosis
- Heat intolerance, sweating, warm skin, malabsorption
- Cardiac - palpitation, tachycardia, CHF
- Menstrual disturbances
- Neuromuscular - Tremor, muscle weakness
- Ocular - thyroid ophthalmopathy
Diffuse goiter (Graves’ Disease)
- Autoimmune disease.
- Thyrotoxicosis with smooth symmetrical enlargement of thyroid.
- Infiltrative ophthalmopathy with exophthalmus in 40%
- of patients.
- Lab findings - increased T4 & T3, decreased TSH.
- Radioactive study- Diffuse uptake of radioactive Iodine.
- Most common cause of endogenous hyperthyroidism.
- Triad of clinical findings:
- - diffuse enlargement of thyroid
- - infiltrative ophthalmopathy (exophthalmos)
- - Infiltrative dermatopathy (periorbital myxedema)
Histology of Diffuse goiter (Graves’ Disease)
- Diffuse hyperplasia of thyroid follicular cells.
- Papillary hyperplasia.
- Scalloped appearance of the edges of the colloid.
- Lymphoid follicles.
Risk factors of malignant/neoplastic thyroid nodules
- Solitary nodule.
- Cold nodules - Up to 10% of cold nodules prove to be malignant.
- Younger patients.
- History of previous radiation to the neck.
- Incidence 3-5%, and 50% in autopsy cases.
- Sometime extends in the mediastinum.
- Pressure effect on trachea.
- Endemic (iodine deficiency) and sporadic.
- Can have gelatinous colloid, cysts.
- Distended follicles of various sizes, filled with colloid, flat follicular epithelium.
- Focal hyperplasia, scalloping
- Most common endocrine malignancy.
- Less than 2% of all human cancers.
- Generally more common in women.
- Associated with radiation exposure and endemic goiters.
- Benign to malignant ratio is 10:1.
- Low mortality rate - 0.4% of cancer deaths.
Clinical manifestations of thyroid neoplasm
- Euthyroid and present with thyroid nodule.
- Symptoms such as dysphagia, dyspnea, and hoarseness usually indicate advanced disease.
- Ipsilateral cervical lymph nodes may be present.
Thyroid neoplasm Diagnosis
- Ultrasound examination of neck and thyroid.
- Blood tests of thyroid function.
- A radioactive thyroid scan.
- A fine needle aspiration biopsy.
- A chest X-ray.
- A CT or MRI scan.
- Follicle derived give rises to well differentiated and anaplastic,
- - Well differentiated give rises to papillary carcinoma and follicular tumors.
- - - Follicular tumors give rises to follicular adenoma and follicular carcinoma.
- C(hief)-cell derived give rise to Medullary carcinoma.
Classification and Incidence of thyroid cancer
- Tumors of follicular cell origin, differentiated
- - Papillary 75%
- - Follicular 10%
- - Hurthle cell 5%
- Tumors of follicular cell origin, undifferentiated
- - Anaplastic 5%
- Tumors of parafollicular cell origin
- - Medullary 5%
- - Lymphoma <1%
- Most common thyroid neoplasm.
- Almost always solitary.
- Well capsulated.
- Uniform follicles within the lesion.
- Compress adjacent normal thyroid tissue.
- No vascular or capsular invasion.
- 10 -15% of thyroid cancer.
- Usually “cold” on radionuclide scan.
- More aggressive.
- Hematologic spread.
- 60% 10 year surviva.l
- Architectural patterns, follicular or solid.
- Capsular invasion.
- Vascular invasion beyond the capsule.
- Integrity of capsule is important in differentiating adenoma from well differentiated follicular carcinoma.
- The most common malignant thyroid tumor (75%).
- Any age.
- Associated with prior radiation.
- Spread via lymphatics – propensity for lymph node
- Excellent prognosis.
- 10 yr survival >95%.
Branching papillae with fibrovascular core, lined by cuboidal to columnar epithelial cells and psammoma bodies.
- Optically clear nuclei (Orphan Annie).
- Intranuclear inclusion and groove.
Papillary carcinoma PROGNOSTIC FACTORS: SAGES
- SEX: WOMEN - good
- AGE: CHIDREN - good
- GRADE: DEDIFFERENTIATION - POOR
- EXTENT: EXTRATHYROID EXTension - POOR
- SIZE: LARGE - POOR
- Neuroendocrine neoplasm originate from calcitonin-producing parafollicular chief cells.
- Solitary or multiple lesions.
- 5-10% of all thyroid cancers.
- 80% Sporadic.
- 20% occurs in the setting of MEN 2A or 2B or as familial tumors.
- Form nests, trabeculae or follicles.
- Polygonal to spindle-shaped cells.
- Acellular amyloid deposits (congo red positive; polarize).
- Positive to Calcitonin immunostain.
- Originates from follicular cells.
- Constitute 5-10% of all thyroid carcinomas.
- Peak incidence – 7th decade.
- Highly fatal, most die within one year.
- Grows rapidly (needs to be treated immediately), spreads locally, invades trachea, esophagus, mediastinum by local invasion.
- Gross - large solid tumor with necrosis and hemorrhage.
- - Multinucleated osteoclast-type giant cells
- - Spindle cell sarcoma-like morphology
- - Squamoid morphology
Thyroid Carcinoma comparison
- Type - %
- - Papillary 75
- - Follicular 15
- - Anaplastic 5
- - Medullary 5
- - Young <45y
- - Middle age
- - elderly
- - Elderly, familial
- - Lymph
- - B.V.
- - Local
- - All
- - Excellent
- - Good
- - Poor
- - variable
Anatomy of Pituitary gland
- In sella turcica of sphenoid bone.
- Weighs about 0.5gm.
- Connected to the Hypothalamus with stalk.
- Composed of:
- - Anterior lobe - Adenohypophysis (80% volume)
- - Posterior lobe - Neurohypophysis (20%); close to third ventricle, optic chiasm, cranial nerves, tumor can affect them.
- Embryology - Roof of the oral cavity and diencephalon come together.
- Pinker in color compared to adenohypophysis.
- Stores and releases hormones secreted by hypothalamus: Oxytocin and Anti Diuretic hormone (ADH).
- Releases hormones:
- Growth hormone (GH)
- Thyroid Stimulating hormone (TSH)
- Adenocorticotropic hormone (ACTH)
- Lutenizing hormone (LH) - target ovary
- Follicle stimulating hormone (FSH) - target ovary
- Prolactin (PRL) - tumor most common
- Melanocyte stimulating hormone (MSH) - pigmentation
- –hypersecretion = hyperthyroidism
- –hyposecretion = hypothyroisism
- –hyposecretion = secondary adrenal insufficiency, Addison’s disease
- –hypersecretion = Cushing’s disease
- •M = poor sperm production
- •F = low estrogen, amenorrhea
- •F = menopause
- •F = no ovulation
- •M = low testosterone
- –hypersecretion = excess pigment
- –hypersecretion = gigantism if during growth or acromegaly after growth
- –hyposecretion = dwarfism
- –hypersecretion = galactorrhea, infertility
- –hyposecretion = poor milk production
- –Hypersecretion = SIADH, Syndrome of Inappropriate ADH Secretion
- –hyposecretion = diabetes insipidus
Histology of Anterior Pituitary
- The pink acidophils (acidophilic cytoplasm) secrete growth hormone (GH) and prolactin.
- The dark purple basophils secrete corticotrophin (ACTH), thyroid stimulating hormone (TSH), and gonadotrophins, i.e. follicle stimulating hormone and luteinizing hormone.
- The pale staining chromophobes have few cytoplasmic granules, but may have secretory activity, secretion is not much affected if tumor is developed from them.
- Hyperpituitarism-related effects:
- - Excessive secretion of tropic hormones.
- - Anterior pituitary adenoma (benign).
- Hypopituitary-related effects:
- - Deficiency of tropic hormones.
- - Destructive processes (injury, inflammation, surgery, radiation).
- Local mass effect:
- - Compressive effect of optic chiasm or third ventricle (Headache, loss of vision, hydrocephalus).
In most cases due to ADENOMA of the anterior lobe.
Benign pituitary adenomas
- Pressure symptoms from glandular enlargement - Headache, seizures, drowsiness, visual defects.
- Hormonal effects
- - Usually stimulatory if functional tumor.
- - May be inhibitory (non-functional with pressure necrosis).
- Most common hormonally active adenomas - prolactinoma, followed by growth hormone related adenoma.
Features common to all pituitary adenomas
- 10% of all intracranial neoplasms & 25% incidental.
- Most sporadic.
- 3% occur with MEN I syndrome (3 P's).
- Usually benign.
- May or may not be functional.
- If Functional, the clinical effects are secondary to the hormone produced, most commonly Prolactin and GH.
- If Non-functional – large size, hypopituitarism (destroy adjacent anterior Pituitary), visual field abnormalities.
- Microadenomas <1 cm, may cause focal bulging.
- Macroadenoma >1 cm, mass effect.
Diagnosis of Pituitary adenoma
- - MRI brain with and without I.V. contrast (include thin cuts through pituitary); Tumor enhances less than gland, more lucent appearance.
- Labs - Prolactin, FSH, LH, GH, ACTH, testosterone, GH, cortisol, IGF-1
- Visual Fields - Performed by an ophthalmologist, temporal fields lost, central field remains.
Morphology of Pituitary adenoma
- Well circumscribed, invasive in up to 30%.
- Size 1cm or more, specially in nonfunctioning tumor.
- Hemorrhage & necrosis seen in large tumors.
- Uniform cells - one cell type (monomorphism), less granular and hard to tell what hormones are secreted.
- No reticulin network, no surrounding nest.
- Rare or absent mitosis.
Pituitary adenoma types
- PRL secreting adenoma (prolactinoma) – Most common, 30% of pituitary adenoma, prolactin level is similar or higher than that during pregnancy.
- ACTH secreting adenoma
- Null cell adenoma
- Gonadotropin-secreting adenoma
- GH-secreting adenoma
- GH and PRL-secreting adenoma
- TSH-secreting adenoma
- Can test by immunohisto stain.
Growth hormone-producing adenoma - Gigantism
- High linear growth due to excessive action of insulin-like growth factor I (IGF-I) while the epiphyseal growth plates are open during childhood.
- Very tall, very long legs and arms.
- Other symptoms - diabetes, arthritis, large jaw & hands, osteoporosis, hypertension, heart failure …..
Growth hormone-producing adenoma - Acromegaly in adults
- After the epiphyseal growth plates are closed.
- Enlarged hands and feet.
- Coarsened, enlarged facial features.
- Impaired vision.
- Enlarged tongue.
- Menstrual cycle irregularities in women.
- Erectile dysfunction in men.
- Enlarged liver, heart, kidneys, spleen and other organs.
- Increased chest size (barrel chest).
Non-functioning adenomas - Null cell adenoma
- 25-30% of patients do not have classical hypersecretory syndromes.
- May grow to a large size before they are detected (mass effect).
- Visual deficits - double vision; Bitemporal hemianopsia.
- Congenital or acquired.
- Loss of 75% of anterior Pituitary to show Symptoms.
- Symptoms include dwarfism, effect of individual hormone deficiencies.
- Acquired causes include:
- 1- Nonsecretory pituitary adenoma.
- 2- Ischemic necrosis e.g. postpartum.
- 3- Iatrogenic by radiation or surgery.
- 4- Autoimmune (lymphocytic) hypophysitis.
- 5- Inflammatory e.g. sarcoidosis or TB …..
- Pituitary gland does not produce enough growth hormones.
- Height lies between 2' 8'' to 4' 8''.
Hypothalamic neurons produce two peptides – ADH and oxytocin. They are stored in axon terminals in neurohypophysis and released with appropriate stimuli.
Posterior Pituitary Syndromes - Abnormal oxytocin secretion
Not associated with any significant abnormality.
Posterior Pituitary Syndromes - associated with ADH
- ADH deficiency - causes Diabetes Insipidus, Excessive urination, dilute urine , due to inability to reabsorb water from the collecting tubules.
- Secretion of inappropriately high level of ADH (SIADH – syndrome of inappropriate ADH) - Causes excessive resorption of water, hyponatremia (low serum level of Sodium).
Metastatic tumors in pituitary
- From Breast, lung ,GI tract.
- Posterior lobe mostly affected.
- Anterior lobe rarely involved.
- 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 of hypofunction or hyperfunction of pituitary and /or visual disturbances, diabetes insipidus.
- Benign & slow growing.
- Low grade circumscribed epithelial tumors.
- Partly cystic and calcified mass.
- Squamoid and columnar epithelium lining cystic spaces filled with oily fluid (keratin debris).
- "Stellate reticulum" and "wet keratin" are prominent features.
Summary of pituitary adenoma
- The most common cause of hyperpituitarism is an anterior lobe pituitary adenoma.
- Pituitary adenomas can be macroadenomas (>1 cm) or microadenomas (<1 cm).
- Macroadenoma – mass effects including visual disturbances.
- Clinically, can be functional or silent.
- Functioning adenomas – associated with distinct endocrine signs and symptoms.
- The two distinctive morphologic features of most adenomas are their cellular monomorphism and absence of a reticulin network.
- A pair of endocrine glands just above the kidney.
- - steroids from cortex.
- - catecholamines from medulla.
- Zona glomerulosa - outer most; mineralocorticoids (aldosterone), associated with SALT.
- Zona fasciculata - glucocorticoids (cortisol), associated with SUGAR.
- Zona reticularis - inner most; estrogens & androgens, SEX.
- Diseases are those of hyperfunction & hypofunction & tumors.
Adrenal cortical Hyperfunction associated syndromes:
- Cushing’s Syndrome (excess of cortisol)
- Adrenogenital or virilizing syndrome (excess of androgen)
- Elevation of cortisol level
- Endogenous causes: all have adrenal hyperplasia
- - Pituitary Cushing syndrome: hypersecretion of ACTH (70% of endogenous hypercortisolism).
- - Ectopic secretion of ACTH by non-pituitary neoplasm (10%) - paraneoplastic Cushing Syndrome, small cell lung cancer.
- - Primary adrenocortical neoplasm and rarely nodular hyperplasia (15-20%)
- Exogenous cause:
- - Steroid Therapy: most common cause of hypercortisolism; iatrogenic; can also cause adrenal atrophy.
Cushing Syndrome Clinical features
- Central obesity 85-90%
- Moon face 85%
- Weakness and fatigability 85%
- Hirsutism 75%
- Hypertension 75%
- Glucose intolerance/diabetes 75%
- Osteoporosis 75%
- Menstrual abnormalities 70%
- Cutaneous striae 50%
- High aldosterone causes Na retention & K excretion, increase blood pressure, Hypokalemia.
- Primary – adrenal (decreases plasma renin)
- - Potential causes – Nodular hyperplasia (60%), Neoplasm (35%), Rarely familial.
- Secondary – extra adrenal (increases plasma renin)
- - Potential causes – Decreased renal perfusion, Arterial hypovolemia and edema, Pregnancy.
- - Primary gonadal disorders
- - Adrenocortical Neoplasms
- - Congenital adrenal hyperplasia
- Neoplasms can occur at any age, frequently malignant.
- Virilization, precocious puberty, ambiguous genitalia.
- Patients have risk for acute adrenocortical insufficiency.
Adrenal cortical tumors
- Encapsulated, solitary, usually yellow.
- Benign or malignant.
- Nonfunctioning or functioning.
- Malignant tumors with necrosis, hemorrhage (≥ 300gms)
- Hypercorticolism is usually more marked with carcinomas than with adenomas or hyperplasia.
- Size variable.
- Local invasion, & the presence of metastases differentiate benign from malignant tumors.
Adrenal cortical adenoma
- Capsulated tumor with uniform or slightly pleomorphic cells, may be eosinophilic or clear cell type
- Spironolactone bodies in hyperaldosteronism
Adrenal cortical carcinoma
Lager than adenoma, non-capsulated with nuclear pleomorphism, mitoses and necrosis.
- Acute :
- 1- Massive adrenal hemorrhage as in anticoagulant
- therapy, DIC, sepsis by N.meningitidis, pseudomonas
- (Waterhouse- Frederickson syndrome).
- 2- Sudden withdrawal of steroid therapy.
- 3- Stress in patient with underlying chronic insufficiency.
- Chronic (Addison’s disease): Progressive destruction of the adrenal by:
- 1- Autoimmune Disorder: 75-90%, may be sporadic.
- 2- Infections e.g. Tuberculosis , fungi ( AIDS).
- 3- Metastatic tumors destroying adrenal e.g. lung, breast , …others.
Addison’s disease - JFK
- - fatigue, lassitude, malaise, weakness, anorexia.
- - postural dizziness, syncope.
- - GI - nausea, vomitting, abdominal pain, diarrhea, constipation.
- - myalgias, arthralgias, rarely flexion contractures.
- - decreased libido, amenorrhea.
- - Weight loss
- - Hyperpigmentation
- - Hypotension
- - Thinning of axillary and pubic hair
- - Vitiligo
- Derived from neural crest.
- Part of sympathetic system.
- Composed of Chromaffin cells secreting catecholamines.
- Diseases are mainly tumors: Pheochromocytoma and Neuroblastoma.
- Neuroendocrine tumor of adrenal medulla.
- Originates from the chromaffin cells along the paravertebral sympathetic chain extending from pelvis to base of skull.
- >95% are abdominal.
- >90% in adrenal medulla.
- Secretes excessive amounts of adrenaline and noradrenaline.
- Diagnosis – increased urinary excretion of free catecholamine and their metabolites (VMA and metanephrins).
- A familial syndrome that predisposes to catecholamine-secreting tumors (MEN2, NF1, VHL).
Pheochromocytom - ‘Rule of 10’
- 10% extra-adrenal (closer to 15%)
- 10% occur in children
- 10% familial (closer to 20%)
- 10% bilateral or multiple (more if familial)
- 10% recur (more if extra-adrenal)
- 10% malignant
- 10% discovered incidentally
Signs & Symptoms of Pheochromocytoma
- The five P’s:
- - Pain (Headache) 80%
- - Perspiration (sweaty) 71%
- - Palpitation 64%
- - Pallor 42%
- - Pressure (HTN) 9% - Surgically correctable
- - - Paroxysms (the sixth P!)
- The Classical Triad:
- - Pain (Headache)
- - Perspiration
- - Palpitations
- - Lack of all 3 virtually excluded diagnosis of pheo in a series of > 21,0000 patients
Morphology of Pheochromocytoma
- Zellballen (small nests or alveolar pattern), trabecular or solid patterns of polygonal / spindle shaped cells in rich vascular network.
- May have mitoses and marked pleomorphism.
- Capsular and vascular invasion common in benign behaving tumors.
- Definitive diagnosis of malignancy – presence of metastasis
- Second most common solid childhood neoplasm, after CNS tumors.
- Usually adrenal but maybe extra-adrenal (sympathetic nervous system).
- Familial or sporadic.
- Associated with deletion of short arm of chromosome 1.
- 90% associated with catecholamine secretion.
- 24hr urinal VMA excretion is helpful in diagnosis.
- Some differentiate (ganglioneuroblastoma) and spontaneously regress.
- Rapid growth & widespread metastasis.
- Treatment complex - surgery, RT, chemotherapy.
Morphology of Neuroblastoma
- Large mass with necrosis.
- Small round blue cell tumor with rosettes.
- Areas of necrosis and calcification.
- May differentiate to ganglion cells.
- Inherited diseases resulting in hyperplasia, adenomas and carcinomas.
- Younger age.
- Multiple endocrine organ Involvement (synchronous or metachronous).
- Asymptomatic stage of endocrine hyperplasia.
- More aggressive and recur.