Pathology of Endocrine System

Dr. Decky Aditya Z

AnatomyThe pituitary gland weighs 0.6 g.It is composed of an anterior adenohypophysial component in apposition with a morphologically, embryologically, and functionally distinct posterior neurohypophysial component.

Anatomy

The Endocrine system is divided into :Endocrine organs dedicated to production of hormones e.g. pituitary,thyroid.etcEndocrine 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 GLANDPituitary 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 ( subunit) in the GNAS1 gene on chromosome 20q13 lead to activation 40% of GH secreting adenomas & less in ACTHG-proteins involved in signal transduction : GDP GTP cAMP

Mutations in subunit interfere with GTPase functionMutations in RAS, overexpression in C- MYC & NM23 inactivation found in more aggressive tumorOther mutations : MEN-1 gene ( Menin)G proteinsGTPase

Features common to all pituitary adenomas :10% of all intracranial neoplasms & 25% incidental 3% occur with MEN syndrome30-50 years of age Primary pituitary adenomas usually benignMay or may not be functionalIf 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

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM)Mass effect of pituitary adenoma

Morphology of pituitary adenomas :Well circumscribed,invasive in up to 30%Size 1cm. or more, specially in nonfunctioning tumorHemorrhage & necrosis seen in large tumorsMicroscopic picture : Uniform cells, one cell type (monomorphism) Absent reticulin networkRare or absent mitosis

Sella turcica with pituitary adenoma

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM)Uniform cells of pituitary adenoma

MorphologyThe usual pituitary adenoma is a well-circumscribed, soft lesion that may, in the case of smaller tumors, be confined by the sella turcica. Larger lesions typically extend superiorly through the sellar diaphragm into the suprasellar region, where they often compress the optic chiasm and adjacent structuresAs these adenomas expand, they frequently erode the sella turcica and anterior clinoid processes. They may also extend locally into the cavernous and sphenoidal sinuses. In as many as 30% of cases the adenomas are grossly nonencapsulated and infiltrate adjacent bone, dura, and (uncommonly) brain. Such lesions are designated invasive adenomas. Foci of hemorrhage and/or necrosis are common in larger adenomas.

Microscopically, pituitary adenomas are composed of relatively uniform, polygonal cells arrayed in sheets, cords, or papillae.Supporting connective tissue, or reticulin, is sparse, accounting for the soft, gelatinous consistency of many lesions. The nuclei of the neoplastic cells may be uniform or pleomorphic.Mitotic activity is usually scanty. The cytoplasm of the constituent cells may be acidophilic, basophilic, or chromophobic, depending on the type and amount of secretory product within the cell, but it is fairly uniform throughout the neoplasm. This cellular monomorphism and the absence of a significant reticulin network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma (Fig. 20-4). The functional status of the adenoma cannot be reliably predicted from its histologic appearance.

Gross view of a pituitary adenoma. This massive, nonfunctional adenoma has grown far beyond the confines of the sella turcica and has distorted the overlying brain. Nonfunctional adenomas tend to be larger at the time of diagnosis than those that secrete a hormone.

Photomicrograph of pituitary adenoma. The monomorphism of these cells contrasts markedly to the mixture of cells seen in the normal anterior pituitary in Figure 20-1. Note also the absence of reticulin network.

Clinical Manifestations of Pituitary AdenomasProlactinomas: amenorrhea, galactorrhea, loss of libido, and infertilityGrowth hormone (somatotroph cell) adenomas: gigantism (children), acromegaly (adults), impaired glucose tolerance, and diabetes mellitusCorticotroph cell adenomas: Cushing syndrome, hyperpigmentationAll pituitary adenomas, particularly nonfunctioning adenomas, may be associated with mass effects and hypopituitarism.

Types of Pituitary AdenomasPreviously classified according to histological picture e.g : Acidophilic AdenomaNow 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 sizeOther 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 :GalactorrheaAmenorrheaDecrease libidoInfertility

2- Growth hormone secreting adenoma : 40% Associated with GNAS 1 gene mutationPersistent secretion of growth hormone leads to secretion of Insulin like GF symptomsComposed 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 adenomaUsually microadenomasHigher chance of becoming malignantChromophobe or basophilic cells Functionless or Cushing s Disease ( ACTH )Bilateral adrenalectomy or destruction may result in aggressive adenoma: Nelsons Syndrome Corticotroph microadenoma Macroadenoma ICP

4- Non functioning adenoma 20% silent or null cell ,nonfunctioning & produce mass effect only

5- Gonadotroph producing LH &FSH- ( 10-15%)- Function silent or is minimal , late presentation mainly mass effect produced. Produce gonadotrophin subunit, - FSH & -LH

6- TSH producing ,(1%) rare cause of hyperthyroidism

7- Pituitary carcinoma - Extremely rare, diagnosed only by metastases.

HYPOPITUITARISM : Loss of 75% of ant. Pituitary Symptoms Congenital or acquired, intrinsic or extrinsicSymptoms include dwarfism, & effect of individual hormone deficiencies. Loss of MSH Decreased pigmentation Acquired causes include : 1- Nonsecretory pituitary adenoma 2- Ischemic necrosis e.g. SHEEHANS SYNDROME (post partum hmg.) sickle cell anemia, DIC, Pituitary apoplexy 3- Iatrogenic by radiation or surgery 4- Autoimmune ( lymphocytic) hypophysitis 5- Inflammatory e.g sarcoidosis or TB ..

6- Empty Sella Syndrome : Radiological term 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

Development from evagination of pharyngeal tissue into neck Abnormal descent Lingual thyroid , subhyoid, substernalWeight 15-20gm. Responsive to stressStructure : varying sized follicles lined by columnar epithelium , filled with colloid, interfollicular C cellsSecretion 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- Hashimotos thyroiditis 3- Iodine deficiency specially in endemic areas 4- Primary idiopathic hypothyroidism 5- Congenital enzyme deficiencies 6- Drugs e.g. iodides, lithium.. 7- Thyroid dysgenesis ( developmental )

Secondary : Pituitary or hypothalamic failure

Hypothyroidism is commoner in endemic areas of iodine deficiencyCRETINISM : 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.

GRAVES DISEASE :

Commonest cause of endogenous hyperthyroidismAge 20- 40 yrs., M: F ratio is 1: 7More 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 , TSHRadioactive study: Diffuse uptake of radioactive I

Pathogenesis of GRAVES DISEASE :Genetic etiology + Autoimmune processesGENETIC EVIDENCE :May be familial 60% concordance in identical twinsSusceptibility is associated with HLA-B8 & - DR3 May exist with other similar diseases e.g. SLE, Pernicious anemia, Diabetes type I, Addisons dis.

IMMUNE MECHANISMS :Antibodies to thyroid peroxisomes & thyroglobulinPatients 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 receptorBoth stimulation & inhibition may coexist

Morphology :Smooth enlargement of gland with diffuse hyperplasia & hypertrophyLining epithelium of acini : Tall & hyperplastic papillaeColloid : Minimal thin colloid with scalloped edge

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HASHIMOTOs THYROIDITIS : Chronic Lymphocytic Thyroiditis

Autoimmune disease characterized by progressive destruction of thyroid tissueCommonest type of thyroiditisCommonest cause of hypothyroidism in areas of sufficient iodine levelsF: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- )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 goiterMay show initial toxicosis ( Hashitoxicosis ).Later marked hypothyroidism.Patients have risk of B-Cell lymphoma

NEOPLASMS of the THYROID : ADENOMAS: Usually single. Well defined capsuleCommonest is follicular Hurthle cell change May be toxicSize 1- 10cm. Variable colour Activating somatic mutation in TSH receptor is identified leading to overproduction of cAMP20% 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

2005 Elsevier Adenoma with intact capsule

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 cellsFew 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 CAPapillary CA : Chromosomal rearrangement in tyrosin kinase receptor gene (RET) on chr.10q11 ret/PTC tyrosine kinase activity ( 1/5 of cases specially in children)Point mutation in BRAF oncogene (1/3-1/2)

Follicular Carcinoma :RAS mutation in of cases ORPAX8- PPAR 1 fusion gene in 1/3 of casesMedullary Carcinoma :RET mutation Receptor activationAnaplastic 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 rearrangement3- Preexisting thyroid disease :Incidence of thyroid CA is more in endemic areasLong standing multinodular goiter Follicular CAHashimotos 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

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

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM) 2005 Elsevier FNA of Papillary CA (nuclear changes)

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

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM) 2005 Elsevier Follicular Carcinoma

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM) 2005 Elsevier Capsular invasion)

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 cellsSecretion of PTH is controlled by level of free calcium

Hyperparathyroidism : Primary OR SecondaryPrimary Hyperparathyroidism:Commonest cause of asymptomatic hypercalcemiaFemale:Male ratio = 2-3 : 1.Causes : Adenoma 75%-80% Hyperplasia 10-15% Carcinoma < 5%Majority of adenomas are sporadic5% 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 HyperparathyroidismAdenomas :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 tumorCompressed 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:Bonresorption by osteoclasts, with fibrosis, cysts formation and hemorrhage Osteitis Fibrosa Cystica Collections of osteoclasts form e Brown TumorsChondrocalcinosis and pseudogout may occur.

Renal system: Ca. Stones. & Nephrocalcinosis.

Metastatic calcification in other organs: Blood vessels & myocardium , Stomach, Lung etc

Hyperparathyroidism, clinical picture50% of patients are asymptomatic.Patients show Ca & PARATHORMONE levels in serumSymptoms 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

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 4 December 2005 01:50 PM) 2005 Elsevier Painful Bones, Renal Stones, Abdominal Groans & Psychic Moans

Secondary Hyperparathyroidism :

Occur in any condition associated with chronic hypocalcemia, mostly chronic renal failure.

Glands are hyperplastic

Renal failure phosphate excretion increased serum phosphate, CaPTH

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

13 mm transversal 9 mm antero-posterior6 mm verticalPeso promedio 0.5 g

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Pathology of Endocrine System