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The Pathology of Pituitary

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1 The Pathology of Pituitary
Doç. Dr. A. Işın DOĞAN-EKİCİ

2 Anatomy The anterior lobe develops from an evagination of Rathke’s pouch (from the primitive oropharynx). The pituitary gland is located in the Sella Turcica in the base of the skull. The anterior pituitary is one of the most vascularized tissues in the body, due to its portal system. Secretion occurs in a 24 hr circadian rhythm . The functions of the pituitary gland are controlled by factors produced in the hypothalamus.

3 Anatomy The anterior lobe develops from an evagination of Rathke’s pouch (from the primitive oropharynx).

4 The pituitary gland is located in the Sella Turcica in the base of the skull.

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6 The anterior pituitary is one of the most vascularized tissues in the body, due to its portal system.

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12 Hypothalamic Hormones Pituitary Hormones Affected
Somatotropin releasing factor Somatotropin Somatotropin releasing factor inhibitor Corticotropin releasing factor (CRH) Corticotropin Thyrotropin-releasing-factor (TRH) Thyrotropin (TSH) Gonadotropin releasing hormone (GRH) FSH and LH Prolactin releasing factor (PRL) Prolactin Prolactin release-inhibiting factor MSH releasing factor Melanocyte-stimulating hormone

13 Topography of Hormone producing cells in the pituitary
The anterior hypophisis can be subdivided into four parts: Two lateral wings produce growth hormone Medial portion: a)Medial posterior ACTH b)Medial Anterior TSH

14 Cell types Anterior Pituitary
Classification by H&E Staining: Eosinophilic Cells: Somatotropes (growth hormone), Lactotropes (Prolactin) Basophilic Cells: Gonadotropes (FSH,LH) Thyrotropes (TSH) Corticotropes (ACTH) Melanotropes (MSH) Chromophob cells: No activity/Prolactin Crook’s hyaline -basophilic change in anterior pituitary cells in Cushing’s Syndrome

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16 Diseases of Pituitary Hormone Production imbalances:
Impaired Synthesis or release Abnormal target tissue interraction Abnormal target tissue response Mass Lesions: Non-functioning Functioning

17 DISEASES of the PITUITARY GLAND
Clinical Classification Hyperpituitarism Hypopituitarism (Simmonds's disease)

18 Multiple endocrine neoplasia syndromes & Hyperpituitarism

19 Multiple endocrine neoplasia syndromes
MEN 1 Syndrome (Werner's Syndrome) MEN 2a Syndrome (Sipple Syndrome) MEN 2b Syndrome (William Syndrome) Common autosomal dominant conditions which predispose patients to certain endocrine tumors. Pre-natal diagnosis is available for these tumor-gene syndromes.

20 MEN 1 Syndrome (Werner's Syndrome)
Hyperparathyroidism 90% Pancreatic Islet Cell Tumors 60% Gastrinoma Insulinoma 10% Vipoma (Vasoactive Intestinal Peptide-Producing Tumor) PPoma (Polypeptidoma) Glucagonoma Pituitary Tumors 5% Prolactinoma GH, ACTH, TSH secreting tumors Thyroid adenoma Adrenal adenoma Carcinoid tumors

21 MEN 2a Syndrome (Sipple Syndrome) MEN 2b Syndrome (William Syndrome)
Medullary Thyroid Carcinoma 100% Pheochromocytoma 50% Hyperparathyroidism 10% MEN 2b Syndrome (William Syndrome) Medullary Thyroid Carcinoma 100% Pheochromocytoma 50% Multiple mucosal neuromas Ganglioneuromatosis of the gut Marfanoid appearance 100%>

22 Hyperpituitarism Too much of one (or may be two or more) of the hormones from the adenohypophysis. This may be due either to: (1) autonomous over-production (tumors of the adenohypophysis: adenoma/carcinoma; ~ 15% of all primary intracranial tumors), or (2) excess production of hypophyseal stimulating factors, or (3) Underproduction of inhibiting factors, or (4) Loss of inhibition following destruction of other endocrine glands.

23 Tumors ANTERIOR LOBE ADENOMAS
Pituitary adenomas constitute 10% of all diagnosed primary intracranial tumors. They can occur at any age, No great sex predominance. They are more common in patients with autosomal dominant multiple endocrine neoplasia (MEN) 1 (Werner's) syndrome.

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26 Pituitary adenomas typically present as one or more of the following:
(1) Endocrine problems (both from hormones produced by the tumor itself and from damage to the rest of the adenohypophysis and/or the neurohypophysis) (2) Visual problems (from an expanding mass impinging on the optic chiasm, i.e., bitemporal hemianopsia) (3) Enlarged sella turcica on skull x-rays (due to expanding masses; large pituitary adenomas eventually erode the sella, clinoid processes, diaphragma sellae, optic nerves and chiasm, and even the cavernous sinuses, nasal sinuses, or brain. (4) Increased intracranial pressure (i.e., headache, nausea and vomiting).

27 (5) Hemorrhage (Hemorrhage into a large pituitary adenoma can produce pituitary apoplexy, which can simulate a berry aneurysm rupture). (6) Infarct (Large tumors may also infarct themselves, leading to remission or destruction of the remaining normal gland as well).

28 Microscopy: Pituitary adenomas are typical endocrine adenomas, i.e. they are composed of cuboidal cells, with round nuclei and a good blood supply. Acidophilic adenomas (eosinophilic adenomas) typically make growth hormone and/or prolactin. Basophilic adenomas typically make ACTH; less often, they make TSH or the gonadotropins. Chromophobe adenomas nothing (null cell adenoma) or may make prolactin.

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30 Pituitary Adenomas Immunocytochemical Classification

31 Causing Growth Hormone Excess
Pituitary Adenomas Causing Growth Hormone Excess somatotroph adenoma mammosomatotroph adenoma Pituitary Adenomas Causing Prolactin Excess lactotroph adenoma psammoma bodies endocrine amyloid acidophilic stem cell adenoma

32 Somatotroph adenoma (GH)

33 Mammosomatotroph adenoma

34 Lactotroph adenoma psammoma bodies a pituitary stone : extensive form of psammoma bodies

35 Lactotroph adenomas produce endocrine amyloid that stains with Congo red

36 Lactotroph adenoma: Intense diffuse positivity for PRL throughout the cell cytoplasm

37 Acidophilic stem cell adenoma: The acidophilia is attributable to mitochondrial accumulation, considered to be a form of oncocytic change

38 Pituitary Adenomas Causing Thyrotropin Excess (TSH)
Pituitary Adenomas Causing ACTH Excess (ACTH) corticotroph adenoma crook's cell adenoma Pituitary Adenomas Causing Gonadotropin Excess (FSH)

39 Clinically Nonfunctioning Pituitary Adenomas
silent somatotroph adenomas silent thyrotroph adenomas silent lactotroph adenomas silent corticotroph adenomas silent gonadotroph adenomas poorly differentiated adenomas Plurihormonal Adenomas Pituitary Carcinoma

40 GROSS APPEARANCE CLINICAL VARIANTS CHARACTERIZATION
Adenomas causing GH excess Acromegaly or gigantism Usually diagnosed early because of the clinical syndrome GH and PRL Often associated with acromegaly and are the most frequent cause of gigantism PRL Amenorrhea and galactorrhea TSH Less than 1% of adenomas ACTH Cushing's disease-accounts for 2/3 of the cases of Nelson's syndrome Gonadtropin (FSH/LH) In general, clinical evidence of excess hormones is rare and tumors usually present with symptoms secondary to the mass effects of the tumor In young women, may present as primary ovarian failure.

41 Radiology

42 Growth hormone adenoma (20%)
Prolactinoma (30%) Men: impotence, loss of libido Women: amenorrhea, loss of libido, infertility Both: Obesity, Galactorrhea Growth hormone adenoma (20%) Children: gigantism Adults: acromegaly Corticotroph cell adenoma (ACTH; 15%) Cushing's disease

43 Hyperprolactinemia (1) Functioning Prolactinomas
(2) Hypothalamic tumors (Stalk effect)* craniopharyngiomas, gliomas, hypothalamic germinomas *Stalk effect: This may be seen with any disease within or near the pituitary gland and stalk that interferes with the delivery of dopamine (a neurotransmitter) from the hypothalamus to the prolactin secreting cells of the pituitary. Therefore, other types of pituitary adenomas, craniopharyngiomas or other tumors or masses may cause modest elevations in prolactin.

44 (3)Medications neuroleptics, antidepressants alfa-methyldopa. (4) Other causes of Hyperprolactinemia pregnancy or in the post-partum period stress (discomfort, exercise, low blood sugar) low thyroid function (hypothyroidism) kidney failure liver failure.

45 Gigantism & Acromegaly
Overproduction of growth hormone causes excessive growth. In children: gigantism In adults: acromegaly. Gigantisim hormone production starts before the growth plates have closed the long bones grow enormously. great stature, and the arms and legs lengthen hypogonadism (delayed puberty, genitals may not develop fully).

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47 Acromegalia prognathism huge brows huge tongue
huge hands (with "spade fingers") develops a deep guttural voice oily skin (extra sebaceous glands), odor joint deformities (degenerative arthritis) barrel chest secondary diabetes sleep apnea cardiomegaly irregular menstrual cycles and galactorrhea.

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50 Cushing's disease Excessive cortisol levels in the blood Etiology
tumors of the pituitary gland (~70%), tumor/hyperplasia* of the adrenal glands ectopic ACTH producing tumors (lung: small cell ca) Production of ACTH by a pituitary tumor ACTH-oma: usually small microadenomas Nelson’s syndrome *Most cases of "idiopathic adrenal hyperplasia" are due to ACTH-omas.

51 Nelson’s syndrome (people who have both their adrenal glands removed for Cushing's disease therapy may develop Nelson's syndrome; ~20%): A Pituitary tumor producing: large amounts of corticotrophin and MSH (hyperpigmentation of the skin) Compress effects of the tumor mass: headache, defects in vision, hypopituitarism (pressure atrophy).

52 Clinical findings Generalized weakness and fatigue Weight gain
Wasting of musculature Menstrual disorders in women (amenorrhea) Decreased fertility and/or libido Hypertension Diabetes mellitus Osteoporosis Kidney stones Depression, mood and behavior disorders Weight gain in face (moon face), above the supraclavicula on back of neck (buffalo hump) thickened trunk Skin findings easy bruising, purplish stretch marks (stria) red cheeks (plethora) hirsutism (face, neck, chest, abdomen, and thighs

53 Adrenal adenoma in Cushing's disease

54 Hypopituitarism

55 Hypopituitarism (Simmonds's disease)
Loss of one or more (often all) of the hormones from the adenohypophysis Panhypopituitarism indicates loss of most or all of the hormones of the adenohypophysis.

56 Etiology of the Hypopituitarism
Causes affecting primarily the hypothalamus: Tumors of the hypothalamus Inflammatory conditions Head injuries Surgical damage Causes affecting primarily the pituitary gland: Empty sella syndrome Pituitary tumors (adenoma, craniopharyngioma, metastasis) Inadequate blood supply (severe bleeding, thrombus, anemia)  infarction  Sheehan’s syndrome Infections and inflammatory conditions (mycosis, Tb, syphilis, sarcoidosis) Amyloidosis Irradiation Surgical removal of the gland Autoimmune pathology (Lymphocytic hypophysitis: rare; most patients are postpartum women).

57 Pituitary tumors (adenoma, craniopharyngioma, metastasis)
Inadequate blood supply (severe bleeding, thrombus, anemia)  infarction  Sheehan’s syndrome Pressure atrophy

58 Panhypopituitarism Clinical findings: weight loss lack of tanning
sexual dysfunction weakness, easy fatigability lack of resistance to stress axillary and pubic hair loss low blood pressure disturbance of visual fields.

59 Empty sella syndrome Pressure atrophy
Slow crushing of the gland by CSF pressure Some of these patients develop pituitary insufficiency. Other reasons: old Sheehan's syndrome total necrosis of an old adenoma previous surgery.

60 Sheehan's pituitary necrosis
(Postpartum pituitary necrosis) Occurs when shock complicates a problem delivery The drop in blood pressure results in inadequate blood supply to the gland (its vessels squeezed half-shut). Sickle cell disease Temporal arteritis Trauma.

61 PITUITARY DWARFISM Failure to produce normal amounts of growth hormone in childhood results in miniature, well-proportioned people. Idiopathic Genetic syndromes Laron dwarves short, frontal bossing the defect is in the growth hormone receptors Pygmies (pituitary dwarfism type II) tissues that do not respond well to growth hormone.

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63 Growth Hormone Deficiency (in childhood):
a lack of growth hormone leads to poor overall growth short height (dwarfism). Deficiency of Gonadotropins (follicle-stimulating hormone and luteinizing hormone): in premenopausal women: amenorrhea, infertility vaginal dryness loss of some female sexual characteristics. in men: atrophy of the testes decreased sperm production  infertility loss of some male sexual characteristics. Kallmann's syndrome : Deficiencies of luteinizing hormone and follicle-stimulating hormone -a cleft lip or palate -color-blind, -unable to sense smells.

64 Thyroid-stimulating Hormone Deficiency: Corticotropin Deficiency:
Underactive thyroid gland (hypothyroidism) confusion, intolerance to cold, weight gain, constipation, dry skin, partial anodontia. Corticotropin Deficiency: Underactive adrenal gland (Addison's disease) fatigue, low blood pressure, low levels of sugar in the blood low tolerance for stress can be fatal.

65 Prolactin Deficiency:
reduces or eliminates lactation Sheehan's syndrome rare complication of childbirth excessive blood loss and shock during childbirth  pituitary infarction  inability to produce breast milk (lactation) fatigue, loss of pubic and underarm hair.

66 Polyglandular deficiency syndromes
Hereditary or Autoimmune disorders Type 1 (in children): Underactive glands: Parathyroids Adrenals Complications: Diabetes Hepatitis Gallstones Malabsorption Fungus infections Hair loss Type 2 (in adults): Underactive glands: Thyroid Adrenals Complications: Diabetes Type 3 (in adults):

67 CRANIOPHARYNGIOMA Benign tumor of Rathke's pouch remnants
Occurs just above the pituitary and sella turcica It is locally aggressive but does not metastasize like the closely-related ameloblastoma of the jaws The optic nerves and chiasm, and then the hypothalamus, are damaged.

68 Most patients are under twenty, but no strict age predilection.
Grossly, the tumor is usually filled with little cysts which contain an unsavory, cholesterol-rich fluid ("machine oil"). Microscopically, the tumor generally recalls developing tooth enamel, with areas of columnar cells (ameloblasts), stellate mesenchyme, calcification, sometimes stratified squamous stuff and/or bone.

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70 Posterior Lobe Diseases
Posterior lobe secretes: Antidiuretic hormone (ADH) which acts in the kidney to retain fluid. Oxytocin Most common pathology is: ADH deficiency  causes Diabetes Insipidus

71 DIABETES INSIPIDUS Polyuria, polydipsia and dehydration
can't concentrate urine Causes within the sella compression by pituitary adenoma pituitary infarction from any cause pituitary ablation (surgical, radiation) sarcoidosis mutant ADH (autosomal dominant; or acquired in chronic lithium administration or other serious renal medullary disease).

72 Causes above the sella old bacterial meningitis
damage from encephalitis meningeal tuberculosis hypophyseal glioma or germinoma craniopharyngioma metastatic cancer skull trauma/fracture nephrogenic diabetes insipidus (the inability of the kidney to respond to ADH).

73 SYNDROME OF INAPPROPRIATE ADH PRODUCTION
Almost always due to : ectopic ADH production by a tumor oat cell carcinoma carcinoid, thymoma, lymphoma widespread pulmonary Tbc produces excess ADH.

74 PITUITARY-HYPOTHALAMIC SYNDROMES
These result from abnormal function of the hypothalamus, reflected in problems with sexual development. Fröhlich's syndrome (adiposogenital dystrophy) is hypothalamic hypogonadism + obesity. Affected boys are obese show a female pattern of fat distribution, dwarfism retarded sexual development.

75 Bardet-Biedl syndrome (Laurence-Moon-Biedl")
retinitis pigmentosa, polydactyly, similar picture to Fröhlich's. Kallmann's syndrome a brain malformation with anosmia (no sense of smell) Fröhlich's findings.

76 McCune-Albright syndrome
with cutaneous café-au-lait ("coffee with milk") spots, polyostotic fibrous dysplasia, precocious puberty, caused by a curious hypothalamic hamartoma that produces LH-releasing hormone. Septo-optic dysplasia multiple birth defects including several malformations of the forebrain.

77 PITUITARY NON-DISEASES
Little pituitary infarcts common in patients who die with intracranial problems. Crooke's hyaline change dense cytoskeleton in pituitary cells which ordinarily make ACTH, when they have suffered chronic suppression by exogenous glucocorticoid administration: Iatrogenic, from an autonomous adrenal adenoma (Cushing’s).

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