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.

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

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

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.

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.

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).

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.

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.

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.

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).