The Pathology of Pituitary

Doç. Dr. A. Işın DOĞAN-EKİCİ

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.

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.

Hypothalamic Hormones Pituitary Hormones Affected

Somatotropin releasing factor Somatotropin

Somatotropin releasing factor inhibitor Somatotropin

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 Prolactin

MSH releasing factor Melanocyte-stimulating hormone

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

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

Diseases of Pituitary

• Hormone Production imbalances:• Impaired Synthesis or release• Abnormal target tissue interraction• Abnormal target tissue response• Mass Lesions:• Non-functioning• Functioning

DISEASES of the PITUITARY GLAND

Clinical Classification

• Hyperpituitarism• Hypopituitarism (Simmonds's

disease)

Multiple endocrine neoplasia syndromes

&

Hyperpituitarism

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.

Hyperparathyroidism 90%

Pancreatic Islet Cell Tumors 60%

Gastrinoma 60%

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

MEN 1 Syndrome (Werner's Syndrome)

MEN 2a Syndrome (Sipple Syndrome)

Medullary Thyroid Carcinoma

100%

Pheochromocytoma 50%

Hyperparathyroidism 10%

MEN 2b Syndrome (William Syndrome)Medullary Thyroid Carcinoma 100%

Pheochromocytoma 50%

Multiple mucosal neuromas 100%

Ganglioneuromatosis of the gut

100%

Marfanoid appearance 100%>

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.

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.

• 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).

• (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).

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.

Pituitary AdenomasImmunocytochemical Classification

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

Somatotroph adenoma (GH)

Mammosomatotroph adenoma

Lactotroph adenomapsammoma bodies

a pituitary stone :extensive form of psammoma bodies

Lactotroph adenomas produce endocrine amyloid that stains with Congo red

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

Acidophilic stem cell adenoma:

The acidophilia is attributable to mitochondrial accumulation, considered to be a form of oncocytic

change

Pituitary Adenomas Causing Thyrotropin Excess (TSH)

Pituitary Adenomas Causing ACTH Excess (ACTH)

• corticotroph adenoma• crook's cell adenoma

Pituitary Adenomas Causing Gonadotropin Excess (FSH)

Clinically Nonfunctioning Pituitary Adenomas

• silent somatotroph adenomas• silent thyrotroph adenomas• silent lactotroph adenomas• silent corticotroph adenomas• silent gonadotroph adenomas• poorly differentiated adenomas

Plurihormonal AdenomasPituitary Carcinoma

GROSS APPEARANCECLINICAL VARIANTS

CHARACTERIZATION

Adenomas causing GH excess

Acromegaly or gigantismUsually diagnosed early because of the clinical syndrome

GH and PRLOften associated with acromegaly and are the most frequent cause of gigantism

PRL Amenorrhea and galactorrhea

TSH Less than 1% of adenomas

ACTHCushing'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 tumorIn young women, may present as primary ovarian failure.

Radiology

• 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

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.

• (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.

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).

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.

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.

• 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).

Clinical findings

• 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

• Generalized weakness and fatigue

• Wasting of musculature • Menstrual disorders in

women (amenorrhea) • Decreased fertility and/or

libido• Hypertension • Diabetes mellitus• Osteoporosis• Kidney stones• Depression, mood and

behavior disorders

Adrenal adenoma in Cushing's disease

Hypopituitarism

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.

Etiology of the Hypopituitarism• 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).

• Causes affecting primarily the hypothalamus:

• Tumors of the hypothalamus

• Inflammatory conditions

• Head injuries• Surgical

damage

Pituitary tumors (adenoma, craniopharyngioma, metastasis)

Inadequate blood supply (severe bleeding, thrombus, anemia) infarction Sheehan’s syndrome

Pressure atrophy

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.

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.

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.

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.

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.

Thyroid-stimulating Hormone 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.

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.

Polyglandular deficiency syndromesHereditary or

Autoimmune disordersType 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):• Underactive glands:

• Thyroid• Complications:

• Diabetes

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.

• 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.

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

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).

• 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).

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.

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.

• 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.

• 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.

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).