GENERAL PATHOLOGY

Pathology of the Pituitary, Pineal Gland and MEN Syndromes Block 5

Joaquin Antonio S. Patag, MD | January 8, 2023 GPT 5.06

OVERVIEW
I. Pituitary Gland II. Pineal Gland
A. Anatomy A. Anatomy
B. Lesions of the Pituitary Gland B. Neoplasms
C. Hypopituitarism III. MEN Syndromes
D. Posterior Pituitary Syndromes A. Types

*TG Note: This trans is purely lecture based. Kindly refer to the ppt (linked
in the workbook) for additional speaker notes that Doc included but did
not mention in class. Please be guided accordingly.

Figure 1. Anatomy of the Pituitary Gland: (A) Pituitary gland found within
ABBREVIATIONS the sella turcica at the base of the brain. (B) The pituitary gland is divided
ACTH Adrenocorticotropic hormone into 2 lobes: the Anterior (adenohypophysis) and Posterior
ADH Antidiuretic hormone (neurohypophysis) lobes.

AVP Arginine vasopressin

A. Anterior Pituitary / Adenohypophysis
CRH Corticotropin-releasing hormone
● Constitutes 80% of the gland
DI Diabetes Insipidus
● Produces trophic hormones
FSH Follicle stimulating hormone
○ These stimulate the production of hormones from the
GH Growth Hormone thyroid, adrenal, and other glands
GH-RIH Growth hormone–release inhibiting hormone ● Composed of epithelial cells derived embryologically from
GHRH Growth hormone–releasing hormone the developing oral cavity
GnRH Gonadotropin-releasing hormone ● In routine histologic sections: it contains a colorful array of
LH Luteinizing Hormone cells that variously have eosinophilic cytoplasm (acidophils),
MSH Melanocyte-stimulating hormone basophilic cytoplasm (basophils), or poorly staining
PIF Prolactin inhibitory factor cytoplasm (chromophobe cells)
POMC Pro-opiomelanocortin ● Detailed studies have demonstrated that the distinct
PRL Prolactin staining properties of these cells are related to the presence
SIADH Syndrome of Inappropriate ADH of different polypeptide hormones within their cytoplasm
that control the activity of other endocrine glands.
TRH Thyrotropin-releasing hormone
TSH Thyroid-stimulating hormone
Hormones Secreted by the Anterior Pituitary
● Production of most pituitary hormones is controlled by
I. THE PITUITARY GLAND
positively and negatively acting factors from the
Anatomy of the Pituitary Gland
hypothalamus, which are carried to the anterior pituitary by
● Small, bean-shaped structure
the portal venous plexus
● Lies at the base of the brain within the sella turcica [Fig 1(A)]
● While most hypothalamic factors promote pituitary hormone
○ Sella turcica: cavity/ depression in the sphenoid bone
release, others (e.g., somatostatin and dopamine) are
that is occupied by the pituitary gland
inhibitory.
○ Since it is found at the base of the brain → tumors can
● Rarely, signs and symptoms of pituitary disease may be
be accessed through the nose → a treatment strategy for
caused by overproduction or underproduction of
pituitary tumors
hypothalamic factors, rather than a primary pituitary
● Function is controlled by the hypothalamus
abnormality.
○ Hypothalamus and pituitary gland are connected via a
● The anterior pituitary releases 6 hormones that are, in turn,
stalk containing axons extending from the hypothalamus
under the control of various stimulatory and inhibitory
and a rich venous plexus
hypothalamic releasing factors
● Hypothalamus + pituitary gland → central role in regulating
function of most of the other endocrine glands Table 1. The 5 hormones released by the anterior pituitary and their
corresponding releasing factors. ⭐
Fig. 1 (B): Hypothalamic Releasing
● Pituitary gland is made up of two lobes: Hormone Controlled
Factors
1. Anterior Lobe (adenohypophysis) Stimulatory Releasing Factors
2. Posterior lobe (neurohypophysis) thyrotropin-releasing hormone Thyroid-stimulating hormone
● The 2 lobes are morphologically and functionally distinct (TRH) (TSH)
● Plexus of arteries and veins allows for communication
corticotropin-releasing Adrenocorticotropic hormone
between hypothalamus and pituitary
hormone (CRH) (ACTH)
○ Compared to the anterior lobe, the posterior lobe
growth hormone–releasing
receives axonal processes from the hypothalamus → Growth hormone (GH*)
hormone (GHRH)
hormones come directly from the hypothalamus
Follicle stimulating hormone
gonadotropin-releasing
(FSH) & Luteinizing hormone
hormone (GnRH)
(LH)

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Inhibitory Releasing Factors muscle, facilitating parturition (uterine

prolactin inhibitory factor (PIF) labor).
Prolactin (PRL)
or dopamine ○ oxytocin released on nipple stimulation
growth hormone–release in the postnatal period acts on the
inhibiting hormone (GH-RIH) or GH* smooth muscles surrounding the
somatostatin lactiferous ducts of the mammary glands
*GH is influenced by both GHRH and GH-RIH and facilitates lactation
○ Synthetic oxytocin can be given to
● There are 6 terminally differentiated cell types in the pregnant women to induce labor.
anterior pituitary, each of which is defined by the hormones ● Most important function: conserve water
that it synthesizes: and prevents diuresis during dehydration
and hypovolemia
Table 2. The different hormone producing cells of the anterior pituitary. ⭐ ● Release is stimulated by decreased blood
Cell Type Hormone/s produced pressure that is sensed by baroreceptors in
Somatotrophs GH AVP / the cardiac atria and carotids
GH ADH ● An increase in plasma osmotic pressure
Mammosomatotroph
PRL detected by osmoreceptors also triggers
Lactotroph PRL ADH secretion.
ACTH ● In contrast, states of hypervolemia and
Corticotroph POMC increased atrial distention result in inhibition
MSH of ADH
Thyrotrophs TSH
FSH
Gonadotrophs
LH

● In women:
○ FSH stimulates the formation of graafian follicles in the
ovary
○ LH induces ovulation and the formation of corpora lutea
in the ovary.
● In males:
○ FSH and LH regulate spermatogenesis and testosterone
production

Figure 3. Anatomy of the Posterior Pituitary Gland.

Clinical Manifestations of Pituitary Disease

● Hyperpituitarism (↑ trophic hormone)
○ Causes: adenomas of anterior pituitary and hypothalamic
Figure 2. Hormones secreted by the Anterior Pituitary. disorders
➢ Ex. prolactin-producing tumor
B. Posterior Pituitary/ Neurohypophysis ● Hypopituitarism (↓ trophic hormone)
● consists of modified glial cells (termed pituicytes) and ○ Causes: ischemic injury, surgery, mass/compression
axonal processes extending from the hypothalamus through effects of pituitary adenomas
the pituitary stalk to the posterior lobe (axon terminals) ○ Damage to cells that produce hormones
● 2 peptide hormones are SECRETED from the posterior ● Symptoms related to local mass effects:
pituitary: ○ Compression of optic chiasm → bitemporal
1. Antidiuretic hormone (ADH) / Arginine vasopressin hemianopsia → loss of vision in lateral temporal fields
(AVP) ○ Hemorrhage into an adenoma → pituitary apoplexy
2. Oxytocin
● these hormones are actually synthesized in the Lesions of the Pituitary Gland
hypothalamus and are transported through axons to the
⭐
Pituitary Adenomas
posterior pituitary Most common cause of hyperpituitarism: pituitary adenoma
⭐
●
in the anterior lobe
Table 3. Hormones secreted by the posterior pituitary ○ Less common causes: pituitary carcinomas and some
Hormone Description / function hypothalamic disorders
● labor contractions and lactation ● Usually affects adults (peak: 35-60 years of age)
● produced in response to cervical dilation ● Microadenoma: < 1 cm
● Example: ● Macroadenoma: > 1 cm
Oxytocin
○ dilation of the cervix in pregnancy ● Prevalence of pituitary adenomas is about 14%, but most
results in oxytocin release → leads to adenomas are clinically silent (pituitary incidentalomas)
contraction of the uterine smooth

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Pathogenesis of Pituitary Adenomas

Activating mutations of the G proteins are one of the most
⭐
●
common causes of pituitary adenomas
● G-proteins play critical roles in signal transduction
○ Heterotrimeric proteins, composed of:
➢ α-subunit: binds guanine nucleotides and interact
with cell surface receptors and intracellular effectors
➢ β- and γ-subunit: noncovalently bind α-subunits
● Signal transduction process:
1. Cell surface receptor activation (e.g., GHRH receptor)
2. Intracellular effectors (e.g., adenyl cyclase)
3. Second messenger generation (e.g., cyclic adenosine
monophosphate, cAMP)
● Upon binding of ligand/hormone to surface receptor:
Figure 5. (A) Gross morphology of pituitary adenomas. (B) This massive,
○ GDP dissociates
nonfunctional adenoma has grown beyond the confines of the sella turcica,
○ GTP binds to Gs α, activating the G-protein distorting the overlying brain.
● Gs α activation generates cAMP, a potent mitogen for
several types of endocrine cells which results in: Histology of Pituitary Adenomas
○ Proliferation/mitosis ● Uniform polygonal cells
○ Hormone synthesis and secretion ● Sheets and cords
● Normally, activated G protein has intrinsic GTPase activity ● Decreased connective tissue reticulin ➝ gelatinous
which hydrolyzes GTP into GDP consistency
○ However, a mutation can make the G protein resistant ● Immunohistochemical stains for hormones are used for
to inactivation wherein GTP is still attached classification
○ This causes constitutive activation of Gs α, persistent ● Low mitotic rate
generation of cAMP, and unchecked cellular proliferation ○ Consistent with its benign nature
● Pituitary carcinomas are very rare

Figure 6. Histology of pituitary adenomas.

*TG Note: Although we don’t need to know the specific histologic features
for pituitary adenomas, we need to know that pituitary adenoma samples
undergo immunohistochemical staining for various markers (FSH, LH,
Figure 4. G-protein signaling in endocrine neoplasia. Mutations that lead to prolactin, growth hormone, ACTH) for them to be classified. ⭐
G-protein hyperactivity are seen in a variety of endocrine neoplasms.
G-proteins (α and βγ subunits) play a critical role in signal transduction,
Types of Pituitary Adenomas
transmitting signals from cell surface receptors (GHRH, TSH, or PTH
receptor) to intracellular effectors (e.g., adenyl cyclase), which then generate A. Lactotroph Adenoma
second messengers (cAMP, cyclic adenosine monophosphate) that stimulate ● Most common type of hyperfunctioning pituitary adenoma
cellular responses. ● ↑ prolactin ➝ causes amenorrhea, galactorrhea, infertility
● Women 20-40 years old
Gross Morphology of Pituitary Adenomas
● Usually soft and well-circumscribed ⭐ ● Not really detected in men because the symptoms are more
apparent in women
● Small adenomas — confined to sella turcica ○ Men do not have galactorrhea
● Larger tumors: ● Prolactinemia may also be caused by damage to the
○ Extend to suprasellar region hypothalamic neurons producing dopamine
○ Compress optic chiasm and cranial nerves ○ Dopamine inhibits prolactin production

Histology of Lactotroph Adenoma

● Pituitary adenomas resemble each other: they show
polygonal cells
● Most are sparsely granulated lactotroph adenomas
(chromophobe cells)
● Positive immunohistochemical stains

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○ Prolactin Treatment of Somatotroph Adenoma

○ Estrogen receptor ● Surgery to remove the adenoma
○ Transsphenoidal pituitary surgery
➢ An endoscope is inserted into the nasal cavity and it
passes through the sphenoid sinus to reach the base
of the brain where the pituitary gland is located. The
tumor is then excised using the endoscope.
● Somatostatin analogues and GH receptor antagonists

Figure 7. (A) Histology of lactotroph adenomas. (B) Antibodies against

prolactin are used during immunohistochemical staining. Positive result =
tissue/sample stains brown. (+) for prolactin confirms that the sample is a
lactotroph adenoma.

*TG Note: Doc said again not that there is no need to memorize the histology.

Figure 9. Transsphenoidal pituitary surgery.

B. Somatotroph Adenoma
● 2nd most common type of hyperfunctioning pituitary Histology of Somatotroph Adenoma
adenoma ● There are two subtypes of Somatotroph Adenomas
● Secretes growth hormone (GH) ● Densely granulated subtype
○ Stimulates the hepatic hepatic secretion of insulin-like ○ Monomorphic, eosinophilic cells
growth factor-1 (IGF-1) ○ Strongly positive for GH
● Cause gigantism in children and acromegaly in adults ● Sparsely granulated subtype
○ Chromophobe cells
Clinical Manifestations of Somatotroph Adenoma ○ Weakly stains with GH
● Gigantism ○ Has a characteristic paranuclear glossy inclusion known
○ Generalized increase in body size with as a fibrous body, composed of intermediate filaments
disproportionately long arms and legs that stain for cytokeratin
○ Occurs due to the elevated levels of GH (and IGF-1) in
children before the epiphyses have closed
● Acromegaly
○ Occurs when the levels of GH and IGF-1 are increased
after closure of the epiphyses (in adults)
○ Growth of skin, soft tissues, viscera, bones of face, hands
and feet
○ Bone density may increase (hyperostosis) in the spine
and the hips Figure 10. Histology of Somatotroph Adenoma.
○ Enlargement of the jaw results in its protrusion
(prognathism) and broadening of the lower face
C. Corticotroph Adenoma
● GH excess can also be associated with a variety of other
● ↑ production of ACTH ➝ ↑ adrenal secretion of cortisol ➝
disturbances:
Cushing syndrome
○ Gonadal dysfunction, diabetes mellitus, generalized
● Cushing disease if hypercortisolism is caused by excessive
muscle weakness, hypertension, arthritis, congestive
production of ACTH by the pituitary
heart failure, and an increased risk of gastrointestinal
● Nelson syndrome
cancers
○ After surgical removal of adrenals for treatment of
Cushing syndrome
○ Loss of the inhibitory effect of adrenal corticosteroids on
a corticotroph microadenoma
○ No hypercortisolism (due to absent adrenals)
○ Leads to mass effects and hyperpigmentation (↑
melanotropin)

Clinical Features of Cushing’s Syndrome

● Figure 8. (A) Somatostatin-growth hormone (GH)-insulin-like
growth factor (IGF-1) axis. (B-D) Clinical manifestations of ● Early stages: hypertension and weight gain
Somatotroph adenoma: (B) Gigantism, (C) Prognathism, and (D) ● Late Stages:
Acromegaly. ○ Central pattern of adipose tissue deposition ➝ truncal
obesity, moon facies, and buffalo hump
Diagnosis of Somatotroph Adenoma ○ Atrophy of fast-twitch (type 2) myofibers ➝ decreased
● ↑ GH and IGF-1 levels muscle mass and proximal limb weakness.
○ Tested via a blood test ○ Striae due to loss of collagen and increased
● Failure to suppress GH production in response to oral susceptibility to fractures due to resorption of bones.
glucose ○ Skin is thin, fragile, and easily bruised; wound healing is
poor

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diplopia, and acute hypopituitarism.

➢ A neurosurgical emergency
○ Ischemic necrosis of the pituitary (Sheehan syndrome)

Figure 11. Clinical manifestations of Cushing’s Syndrome.

Histology of Corticotroph Adenoma

● Basophilic (densely granulated) most often
● Positive staining for periodic acid-Schiff (PAS) due to
carbohydrate in proopiomelanocortin (POMC), the precursor
of ACTH
● Nuclear TPIT is also positive in the neoplastic cells,
consistent with corticotroph lineage
Figure 14. The hypothalamus and pituitary gland. Any damage to these
structures would cause hypopituitarism

Causes of Hypopituitarism
a. Sheehan Syndrome / Ischemic Necrosis of the Pituitary
● Most common form of ischemic necrosis of the anterior
pituitary which usually affects postpartum women.
● During pregnancy, the anterior pituitary enlarges to almost
twice its normal size.
Figure 12. Histology of Corticotroph Adenoma. ● This physiologic expansion is not accompanied by an
increase in blood supply from the low-pressure venous
Less Common Anterior Pituitary Tumors system; hence, there is relative hypoxia
● Gonadotroph (LH- and FSH-producing) adenoma ● Any further reduction in blood supply caused by postpartum
● Thyrotroph (TSH-producing) adenoma hemorrhage or shock may precipitate infarction of the
● Plurihormonal adenoma (secrete multiple hormones) anterior lobe.
● Null cell adenoma – no hormonal differentiation ● Risk factors involved:
● Pituitary carcinoma – rare (<1%) ○ Small Sella size
● Pituitary blastoma ○ Coagulation disorders
○ Home conducted delivery
○ Advanced maternal age

Figure 15. Mechanism of Sheehan syndrome

Figure 13. Histology of a Gonadotroph adenoma.

b. Rathke Cleft Cysts
● Cystic remnants of the embryonic Rathke pouch
Hypopituitarism
○ Recall: Rathke pouch is the diverticulum of the pharynx
● Decreased secretion of pituitary hormones
which gives rise to the anterior pituitary
● Mostly due to destruction of anterior pituitary
● These cysts can accumulate proteinaceous fluid and expand,
○ Tumors and other mass lesions
compromising the normal gland
➢ Pituitary adenomas, other benign tumors,
malignancies, and cysts can cause damage by
exerting pressure on adjacent normal pituitary cells
○ Traumatic brain injury and subarachnoid hemorrhage
○ Pituitary surgery or radiation
○ Pituitary apoplexy
➢ Sudden hemorrhage of a pituitary adenoma
➢ Causes abrupt onset of excruciating headache,

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● Although total body water is increased, blood volume

normal, and peripheral edema does not develop

Figure 17. SIADH vs DI

II. THE PINEAL GLAND

Anatomy of the Pineal Gland
● Small, pinecone shaped organ
Figure 16. Normal development of the anterior pituitary. Persistence of the ● Between superior colliculi at the base of the brain
cleft shown in the diagram results to Rathke cleft cyst
● composed of a loose, neuroglial stroma enclosing nests of
epithelial-appearing pineocytes
Other Causes of Hypopituitarism ○ Pineocytes
● Empty sella syndrome ➢ cells with photosensory and neuroendocrine
○ Any condition or treatment that destroys part or all of functions (hence the designation of the pineal gland
the pituitary gland, such as ablation of the pituitary by as the “third eye”)
surgery or radiation can result in an empty sella ➢ Silver impregnation stains reveal that these cells
○ Two types of empty sella syndrome have long, slender processes reminiscent of primitive
➢ Primary empty sella: a defect in the diaphragma neuronal precursors intermixed with the processes of
sella allows arachnoid mater and CSF to herniate astrocytic cell
into the sella, expanding the sella and compressing ● Secretes melatonin
the pituitary ○ Principle secretory product of the pineal gland
➢ Secondary empty sella: a mass enlarges the sella ○ controls circadian rhythms, including sleep-wake cycle
and is then either surgically removed or undergoes
infarction, leading to loss of pituitary function
● Hypothalamic lesions
○ Craniopharyngioma
○ Metastasis
○ Brain irradiation
● Inflammatory disorders and infections
● Genetic defects

Posterior Pituitary Syndromes Figure 18. Anatomy of the Pineal Gland.

A. Diabetes Insipidus
● Decreased secretion of ADH Pineal Gland Neoplasms
● Characterized by excessive excretion of dilute urine ● Rare
(polyuria) due to the inability of the kidney to reabsorb water ● Most (50-70%) arise from sequestered embryonic germ
properly cells
● Serum sodium and osmolality are increased by the ● Most common form: germinoma
excessive renal loss of free water, resulting in thirst and
polydipsia PINEALOMA
● Can occur in a variety of conditions, including head trauma, ● Tumors arising from pineocytes
tumors, inflammatory disorders of the hypothalamus and ● Classified as:
pituitary, and surgical complications ○ Pineoblastomas
● Two main types: ➢ Less differentiated, fast growing tumors
○ Central: Diabetes insipidus from ADH deficiency ○ Pineocytomas
○ Nephrogenic: Renal tubular unresponsiveness to ➢ More differentiated, slow-growing and
circulating ADH well-circumscribed tumors
● Small round blue cell tumor
B. Syndrome of Inappropriate ADH (SIADH) secretion
● ADH excess causes over-resorption of free water →
hyponatremia and cerebral edema
● Most common cause: secretion of ectopic ADH by malignant
neoplasms (small-cell carcinoma of the lung)
● Other causes:
○ Drugs that increase ADH secretion
○ CNS disorders including infections and trauma

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↪ Peptic ulcers (Zollinger-Ellison syndrome)

↪ Nephrolithiasis (PTH-induced hypercalcemia)
↪ Galactorrhea (prolactinoma)

B. MEN - 2A (Sipple Syndrome)

● Associated with:
○ Pheochromocytoma – bilateral
○ Medullary thyroid carcinoma
➢ Multifocal and aggressive
➢ Associated with C cell hyperplasia in adjacent
thyroid
↪ Secrete calcitonin
○ Parathyroid hyperplasia
Figure 19. Pineocytoma ➢ Causes hypercalcemia and renal stones
● Caused by gain-of-function mutation in RET protooncogene
III. MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROME
● Group of inherited diseases resulting in proliferative lesions C. MEN - 2B (Multiple Mucosal Neuroma Syndrome)
(hyperplasia, adenoma and carcinoma) of multiple endocrine ● Associated with:
organs ○ Pheochromocytoma
● Differ from sporadic tumors, MEN syndrome is/ occurs in: ○ Medullary thyroid carcinoma – multifocal and aggressive
○ Younger age ○ Marfanoid habitus
○ Multiple organs ➢ Long axial skeleton and hyperextensible joints
○ Multifocal in each organ ○ Neuromas
○ Preceded by hyperplasia ➢ Skin, oral mucosa, eyes, respiratory and GIT
○ More aggressive ● Caused by missense mutation in RET

Figure 20. Affected organs in the different MEN Syndromes Types.

Figure 21. (A) Marfanoid habitus. (B) Neuroma papule beneath the nose.

Types of MEN Syndromes Table 4. Lesions of the different MEN syndromes

A. MEN - 1 (Werner Syndrome) LESION MNEMONIC
● Affected areas: ● Parathyroid
MEN - 1
○ Parathyroid – hyperparathyroidism is the most common Hyperplasia PaPa Pi
manifestation ● Pancreatic Tumor (3Ps)
○ Pancreas ● Pituitary Adenoma
➢ Adenomas ● Parathyroid
↪ Usually no endocrine abnormality (pancreatic Hyperplasia
Pa Me Phe
polypeptide is secreted) MEN - 2A ● Medullary Thyroid
(2Ps and 1M)
➢ In those that have endocrine abnormality Carcinoma
(symptomatic): ● Pheochromocytoma
↪ Zollinger-Ellison syndrome (gastrinoma) ● Marfanoid body
↪ Hypoglycemia habitus
MaMe Phe
↪ Neurologic (insulinomas) MEN - 2B ● Medullary Thyroid
(1P and 2Ms)
○ Pituitary Carcinoma
➢ Prolactinoma ● Pheochromocytoma
↪ Most common tumor
↪ Most common type of hyperfunctioning pituitary
adenoma
● Caused by mutations in MEN1 tumor suppressor gene,
which encodes menin
○ Manifestations result from overproduced hormones
➢ Combination of 3 symptoms to consider MEN-1:
↪ Hypoglycemia (insulinoma)

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IV. REVIEW QUESTIONS _____8. Upon hormonal testing, a female patient is said to have
Pituitary Gland decreased TSH, T3, and T4. She was then diagnosed with
secondary hypothyroidism. Which of the following choices is
_____1. Which of the following anterior pituitary cell types is LEAST likely to be the cause of his disease
correctly matched with the hormone that it produces? A. Anterior pituitary lesion
A. Somatotroph : ADH B. Surgical complications involving the posterior pituitary
B. Gonadotroph : GH C. Postpartum necrosis
C. Mammosomatotroph : FSH D. Sheehan syndrome
D. Corticotroph : ACTH
MEN Syndrome

_____2. Which of the following statements is false regarding the

_____9. Compared to sporadic tumors, which is TRUE of MEN
pathogenesis of pituitary adenomas?
syndrome:
A. G-proteins play critical roles in signal transduction
A. Older patients
B. The α-subunit binds guanine nucleotides and interact
B. Single organs
with cell surface receptors and intracellular effectors
C. Unifocal in each organ
C. G protein mutations result in the loss of intrinsic
D. Preceded by hyperplasia
GDPase activity which hydrolyzes GDP into GTP
D. Activating G protein mutations result in Gs α
_____10. Parathyroid carcinoma is associated with Sipple
activation, persistent cAMP generation, and unchecked
Syndrome. MEN-2B is associated with Medullary parathyroid
cellular proliferation
carcinoma.
A. Statement 1 is true
Pituitary Lesions
B. Statement 2 is true
_____3. Which of the following statements is true regarding the C. Both statements are true.
histology of pituitary adenomas? D. Both statements are false.
A. Histologically distinct from each other
B. Mitoses are frequently seen in histologic samples ANSWERS
C. Loss of reticulin contributes to its rubbery consistency 1: D 2: C 3: D 4: A 5: A 6: B 7: A 8: B 9: D 10: D
D. Classification is based on immunohistochemical
staining RATIONALE
1: Recall. Only corticotroph is correctly paired with ACTH.
_____4. Damage to the hypothalamic neurons that produce Somatotrophs produce GH, gonadotrophs produce FSH and
dopamine may cause prolactinemia. In order for a pituitary tumor LH, and mammosomatotroph produce GH and PRL.
to be classified as a lactotroph adenoma, it should test positive 2: Recall. G protein mutations result in the loss of intrinsic
prolactin and FSH after immunohistochemical staining. GTPase activity which hydrolyzes GTP into GDP, resulting in
A. Statement 1 is true. Statement 2 is false. impaired G protein inactivation.
B. Statement 1 is false. Statement 2 is true. 3: Recall.
C. Both statements are true. 4: Recall.
D. Both statements are false. 5: Recall. Acromegaly occurs when the levels of GH and IGF-1
are increased after closure of the epiphyses seen in adults.
_____5. A 25-year-old male presents with symptoms of 6: Recall.
gigantism, including disproportionate body growth and elevated 7: Recall.
levels of growth hormone (GH) and insulin-like growth factor 1 8: Decreased levels of TSH involves an underfunctioning
(IGF-1). What is the most likely diagnosis? anterior pituitary rather than posterior pituitary. Remember
A. Acromegaly that the posterior pituitary only secretes two hormones
B. Cushing's syndrome which are ADH and oxytocin
C. Prolactinoma 9: Recall.
D. Gigantism due to somatotroph adenoma 10: Parathyroid hyperplasia is associated with Sipple Syndrome.
MEN-2B is associated with Medullary thyroid carcinoma.
_____6. A 45-year-old male presents with symptoms of excessive
sweating, weight loss, and hypertension. Laboratory tests reveal REFERENCES
elevated levels of adrenocorticotropic hormone (ACTH) and ● Joaquin Antonio Patag, MD. Notes from Pathology of the
cortisol. What is the most likely diagnosis? Pituitary, Pineal Gland and MEN syndromes.
A. Pheochromocytoma
B. Cushing's syndrome MNEMONICS
C. Sipple Syndrome Table 5. Mnemonic for MEN syndrome lesions
D. Sheehan syndrome LESION MNEMONIC
● Parathyroid
_____7. This condition of the posterior pituitary is characterized MEN - 1
Hyperplasia PaPa Pi
by increased urine osmolality and decreased serum osmolality ● Pancreatic Tumor (3Ps)
A. SIADH ● Pituitary Adenoma
B. Rathke Cleft Cyst
● Parathyroid
C. Central DI
Hyperplasia Pa Me Phe
D. Nephrogenic DI MEN - 2A
● Medullary Thyroid (2Ps and 1M)
Carcinoma

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● Pheochromocytoma GnRH FSH & LH

● Marfanoid body Inhibitory Releasing Factors
habitus PIF or dopamine PRL
MaMe PheNe
MEN - 2B ● Medullary Thyroid GH-RIH or somatostatin GH*
(1P and 2Ms)
Carcinoma *repeated
● Pheochromocytoma
SUMMARY
Table S3. The different hormone producing cells of the anterior pituitary. ⭐
Cell Type Hormone/s produced
The Pituitary Gland
Anatomy of the Pituitary Gland Somatotrophs GH
● Small, bean-shaped structure Mammosomatotroph GH PRL
● Lies at the base of the brain within the sella turcica Lactotroph PRL
● Function is controlled by the hypothalamus Corticotroph ACTH POMC MSH
● Made up of 2 lobes: Thyrotrophs TSH
○ Anterior Lobe (adenohypophysis) Gonadotrophs FSH LH
○ Posterior lobe (neurohypophysis)
Table S4. Hormones secreted by the posterior pituitary
Table S1. The 2 lobes of the pituitary gland Hormone Description / function
Anterior Posterior ● labor contractions and lactation
Oxytocin
Other Name Adenohypophysis Neurohypophysis ● produced in response to cervical dilation
Anatomical Composed of epithelial consists of modified glial ● Most important function: conserve water and
AVP /
features cells derived cells (termed pituicytes) prevents diuresis during dehydration and
ADH
embryologically from and axonal processes hypovolemia
the developing oral extending from the
cavity hypothalamus through the Table S5. Clinical manifestations of pituitary disease
pituitary stalk to the Effect on
Clinical
posterior lobe (axon Trophic Cause
Manifestation
terminals hormone
# of hormones adenomas of anterior pituitary
6 0 Hyperpituitarism ↑increase
produced and hypothalamic disorders
# of hormones ischemic injury, surgery,
6 2*
secreted Hypopituitarism ↓ decrease mass/compression effects of
TSH PRL ADH / AVP pituitary adenomas
Hormones ACTH GH Oxytocin Sx related to local mass effects
FSH LH ● Compression of optic chiasm → bitemporal hemianopsia →
Additional Production of most posterior lobe receives loss of vision in lateral temporal fields
Features pituitary hormones is axonal processes from the ● Hemorrhage into an adenoma → pituitary apoplexy
controlled by positively hypothalamus → hormones
and negatively acting come directly from the Lesions of the Pituitary Gland
factors from the hypothalamus Pituitary Adenomas
hypothalamus, which Pituitary adenoma in the anterior lobe is the most common
⭐
●
are carried to the cause of hyperpituitarism
anterior pituitary by the ● Usually affects adults (peak: 35-60 years of age)
portal venous plexus ● Microadenoma: < 1 cm
(refer to succeeding table) ● Macroadenoma: > 1 cm
*hormones are actually synthesized in the hypothalamus and are
transported through axons to the posterior pituitary Pathogenesis of Pituitary Adenomas
Activating mutations of the G proteins are one of the most
⭐
●
common causes of pituitary adenomas
○ Results in the loss of intrinsic GTPase activity, thus
leading to unchecked cellular proliferation

Table S6. Gross morphology and histology of pituitary adenomas

Morphology Description
● Usually soft and well-circumscribed ⭐
● Small adenomas — confined to sella turcica
Figure S1. Hormones secreted by the Anterior Pituitary. Gross
● Larger tumors — extend to suprasellar region
and compress optic chiasm and cranial nerves
Table S2. The 5 hormones released by the anterior pituitary and their
⭐
corresponding releasing factors.
● Uniform polygonal cells: Different types
resemble each other
Hypothalamic Releasing
Hormone Controlled ● Sheets and cords
Factors
● Decreased connective tissue reticulin ➝
Stimulatory Releasing Factors Histology
gelatinous consistency
TRH TSH
● Immunohistochemical stains for hormones are
CRH ACTH used for classification
GHRH GH* ● Low mitotic rate

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 GPT 5.06 Pathology of the Pituitary, Pineal Gland and MEN Syndromes

Figure S2. (A) Gross morphology of pituitary adenomas. (B) This massive,
nonfunctional adenoma has grown beyond the confines of the sella turcica,
distorting the overlying brain. (C-D) Histology of pituitary adenomas.

Table S7. Types of pituitary adenomas: epidemiology, clinical manifestations, and histology
Types Description Clinical Manifestation Histology
● Most common type of ● ↑ prolactin ➝ causes ● Most are sparsely granulated
hyperfunctioning pituitary adenoma amenorrhea, galactorrhea, lactotroph adenomas (chromophobe
● Women 20-40 years old infertility cells)
Lactotroph Adenoma ● Not really detected in men ● Prolactinemia may also be ● Positive immunohistochemical stains
caused by damage to the ● Prolactin
hypothalamic neurons ● Estrogen receptor
producing dopamine
● 2nd most common type of ● Gigantism ➝ Generalized ● 2 subtypes:
hyperfunctioning pituitary adenoma increase in body size with ○ Densely granulated subtype ➝
● Diagnosis: ↑ GH and IGF-1 levels disproportionately long arms Monomorphic, eosinophilic cells;
Somatotroph
tested via a blood test and legs Strongly positive for GH
Adenoma
● Treatment: Transsphenoidal pituitary ● Acromegaly ➝ Growth of skin, ○ Sparsely granulated subtype ➝
surgery soft tissues, viscera, bones of Chromophobe cells; Weakly stains
face, hands and feet with GH
Clinical Manifestations: ● Basophilic (densely granulated) most
● Cushing syndrome: ↑ ACTH production ➝ ↑ adrenal secretion of cortisol often
○ Early stages: ● Positive staining for periodic
➢ hypertension and weight gain acid-Schiff (PAS) due to carbohydrate
○ Late stages: in proopiomelanocortin (POMC), the
➢ Central pattern of adipose tissue deposition ➝ truncal obesity, moon precursor of ACTH
Corticotroph facies, and buffalo hump ● Nuclear TPIT is also positive in the
Adenoma ➢ Atrophy of fast-twitch (type 2) myofibers ➝ decreased muscle mass neoplastic cells, consistent with
and proximal limb weakness. corticotroph lineage
➢ Striae due to loss of collagen and increased susceptibility to fractures
due to resorption of bones.
➢ Skin is thin, fragile, and easily bruised; wound healing is poor
● Nelson Syndrome: No hypercortisolism (due to absent adrenals) ➝ ↑ mass
effects & hyperpigmentation
Less Common ● Gonadotroph (LH- and FSH-producing) adenoma ● Null cell adenoma – no hormonal differentiation
Anterior Pituitary ● Thyrotroph (TSH-producing) adenoma ● Pituitary carcinoma – rare (<1%)
Tumors ● Plurihormonal adenoma (secrete multiple hormones) ● Pituitary blastoma

Figure S3. (A-B) Histology of lactotroph adenomas. (B) Antibodies against prolactin are used
during immunohistochemical staining. Positive result = tissue/sample stains brown. (+) for Figure S4. (A) Somatostatin-growth hormone (GH)-insulin-like
prolactin confirms that the sample is a lactotroph adenoma. (C-D) Histology of Somatotroph growth factor (IGF-1) axis. (B-D) Clinical manifestations of
Adenoma. (E-F) Histology of Corticotroph Adenoma. Somatotroph adenoma: (B) Gigantism, (C) Prognathism, and (D)
Acromegaly.

Hypopituitarism
● Decreased secretion of pituitary hormones ● Pituitary apoplexy
● Mostly due to destruction of anterior pituitary: ○ Sudden hemorrhage of a pituitary adenoma
○ Tumors and other mass lesions due to exertion of pressure on ○ Causes abrupt onset of excruciating headache, diplopia, and
normal cells acute hypopituitarism.
○ Traumatic brain injury and subarachnoid hemorrhage ○ A neurosurgical emergency

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 GPT 5.06 Pathology of the Pituitary, Pineal Gland and MEN Syndromes

○ Pituitary surgery or radiation ○ Ischemic necrosis of the pituitary (Sheehan syndrome)

Sheehan Syndrome Rathke Cleft Cysts Other Causes
● AKA Ischemic Necrosis of the Pituitary ● Cystic remnants of the ● Empty sella syndrome
● Most common form of ischemic necrosis of embryonic Rathke pouch ○ Destruction of part or all of the pituitary gland can
the anterior pituitary ● Cyst can accumulate result in an empty sella
● Usually affects postpartum women proteinaceous fluid and ○ Two types of empty sella syndrome:
● Relative hypoxia during pregnancy due to expand, compromising the ➢ Primary empty sella: diaphragma sella defect
2x enlargement of anterior pituitary but normal gland allows arachnoid mater and CSF to herniate into the
lack of blood supply sella, expanding the sella and compressing the
○ Postpartum hemorrhage or shock may pituitary
precipitate infarction ➢ Secondary empty sella: removal or infarction of a
● Risk factors involved: mass, leading to loss of pituitary function
○ Small Sella size ● Hypothalamic lesions
○ Coagulation disorders ○ Craniopharyngioma
○ Home conducted delivery ○ Metastasis
○ Advanced maternal age ○ Brain irradiation
● Inflammatory disorders and infections
● Genetic defects

Table S8. Lesions of the Posterior Pituitary

Condition ADH Effect Causes Summary of Effects
● Excessive renal loss of free water ● Head trauma
● Dilute urine ● Tumors
Diabetes
↓ Decreased ● Polydipsia and polyuria ● Inflammatory disorders of the
Insipidus
● Can be central (ADH deficiency) or hypothalamus and pituitary
nephrogenic (ADH unresponsiveness) ● Surgical complications
● Over-resorption of free water ● Most common: secretion of
● Concentrated urine ectopic ADH by malignant
Syndrome of
● Hyponatremia and cerebral edema neoplasms
Inappropriate
↑Increased ● Although total body water is ● Drugs that ↑ ADH secretion
ADH (SIADH)
increased, blood volume normal, and ● CNS disorders including
secretion
peripheral edema does not develop infections and trauma
Figure S6. SIADH vs DI

The Pineal Gland

Anatomy of the Pineal Gland Lesions of the Pineal Gland
● Small, pinecone shaped organ ● Rare
● Between superior colliculi at the base of the ● Most common form: Germinoma
brain ● Pinealimo
● Pineocytes: cells with photosensory and ○ Tumors arising from pineocytes
neuroendocrine functions ○ Classified as:
● Secretes melatonin ➢ Pineoblastomas : LESS differentiated, FAST
○ Principle secretory product of the pineal growing tumors
gland ➢ Pineocytomas: MORE differentiated,
○ controls circadian rhythms, including SLOW-growing and well-circumscribed
sleep-wake cycle tumors
Figure S7. Pineocytoma

Table S9. Summary of MEN syndromes

Other Name Cause Affected Area / Lesion Mnemonic Clinical Manifestation
MEN-1 Werner Mutations in MEN1 ● Parathyroid ● Hyperparathyroidism (most common manifestation)
Syndrome tumor suppressor Hyperplasia PaPaPi
gene which ● Pancreatic Tumor ● No endocrine abnormality: Adenoma
encodes menin ● w/ endocrine abnormality:
○ Zollinger-Ellison syndrome (gastrinoma)
○ Hypoglycemia
○ Neurologic (insulinomas)
● Pituitary Adenoma ● Prolactinoma (most common tumor; most common
type of hyperfunctioning pituitary adenoma)

Combination of 3 symptoms to consider MEN-1:

● Hypoglycemia (insulinoma)
● Peptic ulcers (Zollinger-Ellison syndrome)
● Nephrolithiasis (PTH-induced hypercalcemia)
● Galactorrhea (prolactinoma)

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 GPT 5.06 Pathology of the Pituitary, Pineal Gland and MEN Syndromes

MEN-2A Sipple Gain-of-function ● Parathyroid ● Causes hypercalcemia and renal stones

Syndrome mutation in RET Hyperplasia Pa Me
protooncogene ● Medullary Thyroid Phe ● Multifocal and aggressive
Carcinoma ● Associated with C cell hyperplasia in adjacent thyroid
(secrete calcitonin)
● Pheochromocytoma ● bilateral
MEN-2B Multiple Missense mutation ● Marfanoid body ● Long axial skeleton and hyperextensible joints
Mucosal in RET habitus MaMe
Neuroma ● Medullary Thyroid PheNe ● Multifocal and aggressive
Syndrome Carcinoma
● Pheochromocytoma
● Neuroma ● Skin, oral mucosa, eyes, respiratory, and GIT

FREEDOM WALL

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